Heterocyclic inhibitors of ptpn11

ABSTRACT

The present invention relates to compounds which may be useful as inhibitors of PTPN11 for the treatment or prevention of cancer and other PTP-mediated diseases. Disclosed herein are new compounds and compounds based on pyrazolopyrazines and their application as pharmaceuticals for the treatment of disease.

This application claims the benefit of priority of U.S. Provisionalapplication No. 62/343,455, filed May 31, 2016 and U.S. Provisionalapplication No. 62/451,432, filed Jan. 27, 2017, the disclosures of eachare hereby incorporated by reference as if written herein in theirentirety.

Disclosed herein are new compounds and compounds based onpyrazolopyrazines and their application as pharmaceuticals for thetreatment of disease. Methods of inhibition of PTPN11 (SHP2) activity ina human or animal subject are also provided for the treatment diseasessuch as cancer, including leukemia and melanoma, and cancers of thebreast, lung, and colon.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 shows the effect of the compound Example 1 on tumor volume, ascompared to carrier alone.

FIG. 2 shows the effect of the compound Example 1 on body weight, ascompared to carrier alone.

Tyrosyl phosphorylation regulates human cellular processes from celldifferentiation to growth and apoptosis, and others. Tyrosylphosphorylation is regulated by protein-tyrosine kinases (PTK) andprotein-tyrosine phosphatases (PTP). The breakdown of regulationgoverned by PTK and PTP activity is thought to lead to cancer. PTKinhibitors have been developed as potential cancer therapeutic agents.Recent studies disclose a possible role for PTPs in cellular regulationas well. (AJ Barr et al. Cell 2009, 136, 352-363. JN Andersen et al Mol.Cell. Biol. 2001, 21, 7117-7136).

Protein-tyrosine phosphatase non-receptor type 11 (PTPN11, also known asSrc Homology-2 phosphatase (SHP2)) is a non-receptor protein tyrosinephosphatase encoded by the PTPN11 gene. This PTP contains two tandem Srchomology-2 (SH2) domains, which function as phospho-tyrosine bindingdomains, a catalytic domain, and a C-terminal tail. In the basal statethe protein typically exists in an inactive, self-inhibited conformationwith the N-terminal SH2 domain blocking the active site. When stimulatedby signal transduction mediated by cytokines and growth factor bindingof phosphorylated proteins to the SH2 domains the auto-inhibition isrelieved, this makes the active site available for dephosphorylation ofPTPN11 substrates (M G Mohl, B G Neel, Curr. Opin. Genetics Dev. 2007,17, 23-30. K S Grossmann, Adv. Cancer Res. 2010, 106, 53-89. W. Q. Huanget. al. Curr. Cancer Drug Targets 2014, 14, 567-588. C. Gordon et. al.Cancer Metastasis Rev. 2008, 27, 179-192.).

Germ-line and somatic mutations in PTPN11 have been reported in severalhuman disease resulting in gain-of-function in the catalytic activity,including Noonan Syndrome and Leopard Syndrome; as well as multiplecancers such as juvenile myelomonocytic leukemia, neuroblastoma,myelodysplastic syndrome, B cell acute lymphoblastic leukemia/lymphoma,melanoma, acute myeloid leukemia and cancers of the breast, lung andcolon (M G Mohl, B G Neel, Curr. Opin. Genetics Dev. 2007, 17, 23-30).Recent studies have demonstrated that single PTPN11 mutations are ableto induce Noonan syndrome, JMML-like myeloproliferative disease andacute leukemia in mice. These mutations disrupt the auto-inhibitionbetween the N—SH2 domains and the catalytic site allowing constitutiveaccess of substrates to the catalytic site of the enzyme (E. Darian etal, Proteins, 2011, 79, 1573-1588. Z-H Yu et al, JBC, 2013, 288, 10472,W Qiu et al BMC Struct. Biol. 2014, 14, 10).

PTPN11 is widely expressed in most tissues and plays a regulatory rolein various cell signaling events that are important for a diversity ofcell functions that includes proliferation, differentiation, cell cyclemaintenance, EMT transition, mitogenic activation, metabolic control,transcription regulation, and cell migration, through multiple signalingpathways including the Ras-MAPK, the JAK-STAT or the PI3K-AKT pathways(Tajan, M. et. al. Eur. J. Medical Genetics, 2015, 58, 509-525.Prahallad, A. et. al. Cell Reports, 2015, 12, 1978-1985).

Additionally there is growing evidence that PTPN11/SHP2 may beimplicated in immune evasion during tumorigenesis, and hence a SHP2inhibitor could stimulate the immune response in cancer patients (CancerRes. 2015 Feb. 1; 75(3):508-18. T Yokosuka T, J Exp Med. 2012, 209(6),1201. S Amarnath Sci Transl Med. 2011, 3, 111ra120. T Okazaki, PNAS2001, 98:24, 13866-71).

Novel compounds and pharmaceutical compositions, certain of which havebeen found to inhibit PTPN11 (SHP2) have been discovered, together withmethods of synthesizing and using the compounds including methods forthe treatment of PTP-mediated diseases in a patient by administering thecompounds.

In certain embodiments of the present invention, compounds havestructural Formula

or a salt or tautomer thereof, wherein:

a is selected from 0 and 1;

b is selected from 0 and 1;

R₁ is selected from halo, C₆₋₁₀aryl, C₃₋₈cycloalkyl, C₃₋₈cycloalkenyl,and a 5-9 membered heteroaryl group containing 1 to 4 heteroatoms orgroups independently selected from N, C(O), O, and S;

said aryl or heteroaryl of R₁ is optionally substituted with 1 to 5 R₁₂groups independently selected from halo, hydroxy, amino, C₁₋₄alkylamino,C₁₋₄dialkylamino, cyano, C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄hydroxyalkyl,C₁₋₄haloalkyl, C₁₋₄aminoalkyl, C₃₋₈cycloalkyl, C₃₋₈cycloalkenyl,NR₁₅C(O)R₁₃, NR₁₅C(O)OR₁₃, NR₁₃C(O)NR₁₅R₁₆, NR₁₅S(O)R₁₃, NR₁₅S(O)₂R₁₃,C(O)NR₁₅R₁₆, S(O)NR₁₅R₁₆, S(O)₂NR₁₅R₁₆, C(O)R₁₃, C(O)OR₁₃, SR₁₃,S(O)R₁₃, and S(O)₂R₁₃;

R₂, R₃, R₁₀, and R₁₁ are independently selected from hydrogen,C₁₋₄alkyl, and C₃₋₈cycloalkyl;

R₄, R₅, R₈, and R₉ are independently selected from hydrogen, cyano,C₁₋₄alkyl, C₁₋₄alkoxy, amino, hydroxy, C₃₋₈cycloalkyl, halo, andC₁₋₄alkylamino;

R₆ is selected from amino, C₁₋₄aminoalkyl, and C₁₋₄alkylamino;

R₇ is selected from hydrogen, cyano, amido, halo, and hydroxy, or isselected from C₁₋₄alkyl, C₁₋₄hydroxyalkyl, C₃₋₆cycloalkyl, phenyl, and5- or 6-membered heteroaryl, any of which is optionally substituted withone or more R₁₇ groups;

or R₆ and R₇ together with the carbon atom to which they are bothattached form a 3- to 7-membered saturated or unsaturated ring that cancontain 1 to 3 heteroatoms or groups independently selected from N,C(O), O, and S(O)_(m), and that is optionally substituted with one R₁₇group, and that is optionally substituted with one or more R₁₈ groups;

m is selected from 0, 1, and 2;

any two groups selected from R₂, R₃, R₄, R₅, R₇, R₈, R₉, R₁₀ and R₁₁ canform a 5- to 6-membered ring, optionally containing a N, O or Sheteroatom;

any two groups selected from R₂, R₄, R₆, R₈ and R₁₀ can form a directbond, or a 1 or 2 atom carbon bridge;

R₁₃, R₁₅, and R₁₆ are independently selected from hydrogen, C₁₋₄alkyl,and C₃₋₈cycloakyl, wherein said alkyl or cycloalkyl is optionallysubstituted by one or more substituents selected from hydroxy, cyano andhalo; and

each R₁₇ and R₁₈ is independently selected from amino, halo, hydroxy,cyano, trifluoromethyl, trifluoromethoxy, C₁₋₄alkyl, and C₁₋₄alkoxy.

Certain compounds disclosed herein may possess useful PTPN11 inhibitingactivity, and may be used in the treatment or prophylaxis of a diseaseor condition in which PTPN11 plays an active role. Thus, in broadaspect, certain embodiments also provide pharmaceutical compositionscomprising one or more compounds disclosed herein together with apharmaceutically acceptable carrier, as well as methods of making andusing the compounds and compositions. Certain embodiments providemethods for inhibiting PTPN11. Other embodiments provide methods fortreating a PTPN11-mediated disorder in a patient in need of suchtreatment, comprising administering to said patient a therapeuticallyeffective amount of a compound or composition according to the presentinvention. Also provided is the use of certain compounds disclosedherein for use in the manufacture of a medicament for the treatment of adisease or condition ameliorated by the inhibition of PTPN11.

In certain embodiments, R₆ is selected from amino, C₁₋₄aminoalkyl, andmethylamino.

In certain embodiments, each R₁₇ is independently selected from amino,halo, hydroxy, and cyano.

In certain embodiments, each R₁₇ is independently selected from amino,hydroxy, and cyano.

In certain embodiments, R₁₇ is amino.

In certain embodiments, each R₁₈ is independently selected from halo,hydroxy, and cyano.

In certain embodiments, R₁₈ is halo.

In certain embodiments,

R₁ is selected from C₆₋₁₀aryl and a 5- to 9-membered heteroaryl groupcontaining 1 to 4 heteroatoms or groups independently selected from N,C(O), O, and S;

said aryl or heteroaryl of R₁ is optionally substituted with 1 to 5 R₁₂groups independently selected from halo, hydroxy, alkoxy, amino,C₁₋₄alkylamino, C₁₋₄dialkylamino, cyano, C₁₋₄alkyl, C₁₋₄hydroxyalkyl,C₁₋₄haloalkyl, C₁₋₄aminoalkyl, C₃₋₈cycloalkyl, C₃₋₈cycloalkenyl,NR₁₅C(O)R₁₃, NR₁₅C(O)OR₁₃, NR₁₃C(O)NR₁₅R₁₆, NR₁₅S(O)R₁₃, NR₁₅S(O)₂R₁₃,C(O)NR₁₅R₁₆, S(O)NR₁₅R₁₆, S(O)₂NR₁₅R₁₆, C(O)R₁₃, C(O)OR₁₃, SR₁₃,S(O)R₁₃, and S(O)₂R₁₃; and

R₁₃, R₁₅, and R₁₆ are independently selected from hydrogen, C₁₋₄alkyl,and C₃₋₈cycloakyl, wherein said alkyl or cycloalkyl is optionallysubstituted by one or more substituents selected from hydroxy, cyano andhalo.

In certain embodiments,

R₁ is selected from C₆₋₁₀aryl and a 5- to 9-membered heteroaryl groupcontaining 1 to 4 heteroatoms or groups independently selected from N,C(O), O, and S;

said aryl or heteroaryl of R₁ is optionally substituted with 1 to 5 R₁₂groups independently selected from halo, hydroxy, alkoxy, amino,C₁₋₄alkyl, C₁₋₄haloalkyl, and C₁₋₄aminoalkyl; and

R₁₇ is selected from amino, halo, and hydroxy.

In certain embodiments,

R₁ is selected from C₆₋₁₀aryl and a 5- to 9-membered heteroaryl groupcontaining 1 to 4 heteroatoms or groups independently selected from N,C(O), O, and S;

said aryl or heteroaryl of R₁ is optionally substituted with 1 to 5 R₁₂groups independently selected from halo, hydroxy, alkoxy, amino,C₁₋₄alkyl, C₁₋₄haloalkyl, and C₁₋₄aminoalkyl;

R₆ is selected from amino, C₁₋₄aminoalkyl, and C₁₋₄alkylamino;

R₇ is selected from hydrogen, halo, and hydroxy, or is selected fromC₁₋₄alkyl, C₁₋₄hydroxyalkyl, C₃₋₆cycloalkyl, phenyl, and 5- or6-membered heteroaryl, any of which is optionally substituted with oneor more R₁₇ groups.

In certain embodiments,

R₁ is selected from C₆₋₁₀aryl and a 5- to 9-membered heteroaryl groupcontaining 1 to 4 heteroatoms or groups independently selected from N,C(O), O, and S;

said aryl or heteroaryl of R₁ is optionally substituted with 1 to 5 R₁₂groups independently selected from halo, hydroxy, alkoxy, amino,C₁₋₄alkyl, C₁₋₄haloalkyl, and C₁₋₄aminoalkyl; and

R₄, R₅, R₈, and R₉ are independently selected from hydrogen, C₁₋₄alkyl,C₁₋₄alkoxy, amino, hydroxy, C₃₋₈cycloalkyl, and C₁₋₄alkylamino.

In certain embodiments, R₂, R₃, R₄, R₅, R₈, R₉, R₁₀ and R₁₁ arehydrogen.

In certain embodiments,

R₆ and R₇ together with the carbon atom to which they are both attachedform a 3- to 7-membered cycloalkyl ring that is optionally substitutedwith one R₁₇ group, and that is optionally substituted with one or moreR₁₈ groups.

In certain embodiments,

R₁ is selected from C₆₋₁₀aryl and a 5- to 9-membered heteroaryl groupcontaining 1 to 4 heteroatoms or groups independently selected from N,C(O), O, and S;

said aryl or heteroaryl of R₁ is optionally substituted with 1 to 5 R₁₂groups independently selected from halo, hydroxy, amino, C₁₋₄alkylamino,C₁₋₄dialkylamino, C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄haloalkyl, andC₁₋₄aminoalkyl; and

R₁₇ is selected from amino, halo, and hydroxy.

In certain embodiments,

R₁ is selected from C₆₋₁₀aryl and a 5- to 9-membered heteroaryl groupcontaining 1 to 4 heteroatoms or groups independently selected from N,C(O), O, and S;

said aryl or heteroaryl of R₁ is optionally substituted with 1 to 5 R₁₂groups independently selected from halo, hydroxy, amino, C₁₋₄alkylamino,C₁₋₄dialkylamino, C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄haloalkyl, andC₁₋₄aminoalkyl;

R₆ is selected from amino, C₁₋₄aminoalkyl, and C₁₋₄alkylamino; and

R₇ is selected from hydrogen, cyano, amido, halo, and hydroxy, or isselected from C₁₋₄alkyl, C₁₋₄hydroxyalkyl, C₃₋₆cycloalkyl, phenyl, and5- or 6-membered heteroaryl, any of which is optionally substituted withone or more R₁₇ groups.

In certain embodiments,

R₆ and R₇ together with the carbon atom to which they are both attachedform a 3- to 7-membered saturated or unsaturated ring that can contain 1to 3 heteroatoms or groups independently selected from N, C(O), O, andS(O)_(m), and that is optionally substituted with one R₁₇ group, andthat is optionally substituted with one or more R₁₈ groups.

In certain embodiments,

R₆ and R₇ together with the carbon atom to which they are both attachedforms a 3- to 7-membered cycloalkyl ring that is optionally substitutedwith one R₁₇ group, and that is optionally substituted with one or moreR₁₈ groups.

In certain embodiments,

R₆ and R₇ together with the carbon atom to which they are both attachedforms a 3- to 7-membered heterocycloalkyl ring that is optionallysubstituted with one R₁₇ group, and that is optionally substituted withone or more R₁₈ groups.

In certain embodiments,

R₆ and R₇ together with the carbon atom to which they are both attachedforms a 3- to 7-membered heterocycloalkyl ring that is optionallysubstituted with one R₁₇ group.

In certain embodiments,

R₆ and R₇ together with the carbon atom to which they are both attachedform a 3- to 6-membered heterocycloalkyl ring that is optionallysubstituted with one R₁₇ group, and that is optionally substituted withone or more R₁₈ groups.

In certain embodiments,

R₆ and R₇ together with the carbon atom to which they are both attachedform a 3- to 6-membered heterocycloalkyl ring that is optionallysubstituted with one R₁₇ group.

In certain embodiments,

R₆ is C₁₋₄aminoalkyl; and

R₇ is selected from hydroxy, or is selected from C₁₋₄alkyl,C₁₋₄hydroxyalkyl, C₃₋₆cycloalkyl, phenyl, and 5- or 6-memberedheteroaryl, any of which is optionally substituted with one or more R₁₇groups.

In certain embodiments,

R₆ is aminomethyl; and

R₇ is selected from hydroxy, C₁₋₄alkyl, C₁₋₄hydroxyalkyl,C₃₋₆cycloalkyl, phenyl, and 5- or 6-membered heteroaryl.

In certain embodiments,

R₆ is amino; and

R₇ is selected from amido, C₁₋₄alkyl, C₁₋₄hydroxyalkyl, C₃₋₆cycloalkyl,phenyl, and 5- or 6-membered heteroaryl, any of which is optionallysubstituted with one or more R₁₇ groups.

In certain embodiments,

R₆ is amino; and

R₇ is C₁₋₄hydroxyalkyl.

In any of the above embodiments, the amido of R₇ may specifically be—C(O)NH₂.

In certain embodiments,

R₁ is selected from C₆₋₁₀aryl and a 5-9 membered heteroaryl groupcontaining 1 to 4 heteroatoms or groups independently selected from N,C(O), O, and S; and

said aryl or heteroaryl of R₁ is optionally substituted with 1 to 5 R₁₂groups independently selected from halo, hydroxy, alkoxy, amino,C₁₋₄alkylamino, C₁₋₄dialkylamino, cyano, and C₁₋₄alkyl.

In certain embodiments, R₁ is selected from:

and

each R₁₂ is independently selected from halo, hydroxy, amino,methylamino, dimethylamino, cyano, C₁₋₄alkyl, and C₁₋₄alkoxy.

In certain embodiments, R₁ is selected from:

In certain embodiments, R₁ is selected as above, wherein each R₁₂ isindependently selected from halo, hydroxy, C₁₋₄alkyl, and C₁₋₄alkoxy.

In certain embodiments, R₁ is selected from pyridyl, piperazinyl,pyrimidinyl, pyrazolyl, and pyridazinyl.

In certain embodiments, R₁ is phenyl.

In certain embodiments, compounds have structural Formula II:

or a salt or tautomer thereof, wherein:

R₁ is selected from halo, C₆₋₁₀aryl, C₃₋₈cycloalkyl, C₃₋₈cycloalkenyl,and a 5-9 membered heteroaryl group containing 1 to 4 heteroatoms orgroups independently selected from N, C(O), O, and S;

said aryl or heteroaryl of R₁ is optionally substituted with 1 to 5 R₁₂groups independently selected from halo, hydroxy, amino, C₁₋₄alkylamino,C₁₋₄dialkylamino, cyano, C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄hydroxyalkyl,C₁₋₄haloalkyl, C₁₋₄aminoalkyl, C₃₋₈cycloalkyl, C₃₋₈cycloalkenyl,NR₁₅C(O)R₁₃, NR₁₅C(O)OR₁₃, NR₁₃C(O)NR₁₅R₁₆, NR₁₅S(O)R₁₃, NR₁₅S(O)₂R₁₃,C(O)NR₁₅R₁₆, S(O)NR₁₅R₁₆, S(O)₂NR₁₅R₁₆, C(O)R₁₃, C(O)OR₁₃, SR₁₃,S(O)R₁₃, and S(O)₂R₁₃;

R₆ is selected from amino, C₁₋₄aminoalkyl, and C₁₋₄alkylamino;

R₇ is selected from hydrogen, cyano, amido, halo, and hydroxy, or isselected from C₁₋₄alkyl, C₁₋₄hydroxyalkyl, C₃₋₆cycloalkyl, phenyl, and5- or 6-membered heteroaryl, any of which is optionally substituted withone or more R₁₇ groups;

R₁₃, R₁₅, and R₁₆ are independently selected from hydrogen, C₁₋₄alkyl,and C₃₋₈cycloakyl, wherein said alkyl or cycloalkyl is optionallysubstituted by one or more substituents selected from hydroxy, cyano andhalo; and

each R₁₇ is independently selected from amino, halo, hydroxy, cyano,trifluoromethyl, trifluoromethoxy, C₁₋₄alkyl, and C₁₋₄alkoxy.

In certain embodiments, compounds have structural Formula III:

or a salt or tautomer thereof, wherein:

R₁ is selected from halo, C₆₋₁₀aryl, C₃₋₈cycloalkyl, C₃₋₈cycloalkenyl,and a 5-9 membered heteroaryl group containing 1 to 4 heteroatoms orgroups independently selected from N, C(O), O, and S;

said aryl or heteroaryl of R₁ is optionally substituted with 1 to 5 R₁₂groups independently selected from halo, hydroxy, amino, C₁₋₄alkylamino,C₁₋₄dialkylamino, cyano, C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄hydroxyalkyl,C₁₋₄haloalkyl, C₁₋₄aminoalkyl, C₃₋₈cycloalkyl, C₃₋₈cycloalkenyl,NR₁₅C(O)R₁₃, NR₁₅C(O)OR₁₃, NR₁₃C(O)NR₁₅R₁₆, NR₁₅S(O)R₁₃, NR₁₅S(O)₂R₁₃,C(O)NR₁₅R₁₆, S(O)NR₁₅R₁₆, S(O)₂NR₁₅R₁₆, C(O)R₁₃, C(O)OR₁₃, SR₁₃,S(O)R₁₃, and S(O)₂R₁₃;

R₆ is selected from amino, C₁₋₄aminoalkyl, and C₁₋₄alkylamino;

R₇ is selected from hydrogen, cyano, amido, halo, and hydroxy, or isselected from C₁₋₄alkyl, C₁₋₄hydroxyalkyl, C₃₋₆cycloalkyl, phenyl, and5- or 6-membered heteroaryl, any of which is optionally substituted withone or more R₁₇ groups;

R₁₃, R₁₅, and R₁₆ are independently selected from hydrogen, C₁₋₄alkyl,and C₃₋₈cycloakyl, wherein said alkyl or cycloalkyl is optionallysubstituted by one or more substituents selected from hydroxy, cyano andhalo; and

each R₁₇ is independently selected from amino, halo, hydroxy, cyano,trifluoromethyl, trifluoromethoxy, C₁₋₄alkyl, and C₁₋₄alkoxy.

In certain embodiments, compounds have structural Formula IV:

or a salt or tautomer thereof, wherein:

R₁ is selected from halo, C₆₋₁₀aryl, C₃₋₈cycloalkyl, C₃₋₈cycloalkenyl,and a 5-9 membered heteroaryl group containing 1 to 4 heteroatoms orgroups independently selected from N, C(O), O, and S;

said aryl or heteroaryl of R₁ is optionally substituted with 1 to 5 R₁₂groups independently selected from halo, hydroxy, amino, C₁₋₄alkylamino,C₁₋₄dialkylamino, cyano, C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄hydroxyalkyl,C₁₋₄haloalkyl, C₁₋₄aminoalkyl, C₃₋₈cycloalkyl, C₃₋₈cycloalkenyl,NR₁₅C(O)R₁₃, NR₁₅C(O)OR₁₃, NR₁₃C(O)NR₁₅R₁₆, NR₁₅S(O)R₁₃, NR₁₅S(O)₂R₁₃,C(O)NR₁₅R₁₆, S(O)NR₁₅R₁₆, S(O)₂NR₁₅R₁₆, C(O)R₁₃, C(O)OR₁₃, SR₁₃,S(O)R₁₃, and S(O)₂R₁₃; and

R₁₃, R₁₅, and R₁₆ are independently selected from hydrogen, C₁₋₄alkyl,and C₃₋₈cycloakyl, wherein said alkyl or cycloalkyl is optionallysubstituted by one or more substituents selected from hydroxy, cyano andhalo.

In certain embodiments, compounds have structural Formula V:

or a salt or tautomer thereof, wherein:

R₁ is selected from halo, C₆₋₁₀aryl, C₃₋₈cycloalkyl, C₃₋₈cycloalkenyl,and a 5-9 membered heteroaryl group containing 1 to 4 heteroatoms orgroups independently selected from N, C(O), O, and S;

said aryl or heteroaryl of R₁ is optionally substituted with 1 to 5 R₁₂groups independently selected from halo, hydroxy, amino, C₁₋₄alkylamino,C₁₋₄dialkylamino, cyano, C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄hydroxyalkyl,C₁₋₄haloalkyl, C₁₋₄aminoalkyl, C₃₋₈cycloalkyl, C₃₋₈cycloalkenyl,NR₁₅C(O)R₁₃, NR₁₅C(O)OR₁₃, NR₁₃C(O)NR₁₅R₁₆, NR₁₅S(O)R₁₃, NR₁₅S(O)₂R₁₃,C(O)NR₁₅R₁₆, S(O)NR₁₅R₁₆, S(O)₂NR₁₅R₁₆, C(O)R₁₃, C(O)OR₁₃, SR₁₃,S(O)R₁₃, and S(O)₂R₁₃;

R₁₃, R₁₅, and R₁₆ are independently selected from hydrogen, C₁₋₄alkyl,and C₃₋₈cycloakyl, wherein said alkyl or cycloalkyl is optionallysubstituted by one or more substituents selected from hydroxy, cyano andhalo; and

R₁₇ is selected from amino, halo, hydroxy, cyano, trifluoromethyl,trifluoromethoxy, C₁₋₄alkyl, and C₁₋₄alkoxy.

In certain embodiments, compounds have structural Formula VI:

or a salt or tautomer thereof, wherein:

R₁ is selected from halo, C₆₋₁₀aryl, C₃₋₈cycloalkyl, C₃₋₈cycloalkenyl,and a 5-9 membered heteroaryl group containing 1 to 4 heteroatoms orgroups independently selected from N, C(O), O, and S;

said aryl or heteroaryl of R₁ is optionally substituted with 1 to 5 R₁₂groups independently selected from halo, hydroxy, amino, C₁₋₄alkylamino,C₁₋₄dialkylamino, cyano, C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄hydroxyalkyl,C₁₋₄haloalkyl, C₁₋₄aminoalkyl, C₃₋₈cycloalkyl, C₃₋₈cycloalkenyl,NR₁₅C(O)R₁₃, NR₁₅C(O)OR₁₃, NR₁₃C(O)NR₁₅R₁₆, NR₁₅S(O)R₁₃, NR₁₅S(O)₂R₁₃,C(O)NR₁₅R₁₆, S(O)NR₁₅R₁₆, S(O)₂NR₁₅R₁₆, C(O)R₁₃, C(O)OR₁₃, SR₁₃,S(O)R₁₃, and S(O)₂R₁₃;

R₁₃, R₁₅, and R₁₆ are independently selected from hydrogen, C₁₋₄alkyl,and C₃₋₈cycloakyl, wherein said alkyl or cycloalkyl is optionallysubstituted by one or more substituents selected from hydroxy, cyano andhalo;

R₁₇ is selected from amino, halo, hydroxy, cyano, trifluoromethyl,trifluoromethoxy, C₁₋₄alkyl, and C₁₋₄alkoxy; and

R₁₈ is selected from halo, hydroxy, and cyano.

In certain embodiments, compounds have structural Formula VII:

or a salt or tautomer thereof, wherein:

R₁ is selected from halo, C₆₋₁₀aryl, C₃₋₈cycloalkyl, C₃₋₈cycloalkenyl,and a 5-9 membered heteroaryl group containing 1 to 4 heteroatoms orgroups independently selected from N, C(O), O, and S;

said aryl or heteroaryl of R₁ is optionally substituted with 1 to 5 R₁₂groups independently selected from halo, hydroxy, amino, C₁₋₄alkylamino,C₁₋₄dialkylamino, cyano, C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄hydroxyalkyl,C₁₋₄haloalkyl, C₁₋₄aminoalkyl, C₃₋₈cycloalkyl, C₃₋₈cycloalkenyl,NR₁₅C(O)R₁₃, NR₁₅C(O)OR₁₃, NR₁₃C(O)NR₁₅R₁₆, NR₁₅S(O)R₁₃, NR₁₅S(O)₂R₁₃,C(O)NR₁₅R₁₆, S(O)NR₁₅R₁₆, S(O)₂NR₁₅R₁₆, C(O)R₁₃, C(O)OR₁₃, SR₁₃,S(O)R₁₃, and S(O)₂R₁₃;

R₁₃, R₁₅, and R₁₆ are independently selected from hydrogen, C₁₋₄alkyl,and C₃₋₈cycloakyl, wherein said alkyl or cycloalkyl is optionallysubstituted by one or more substituents selected from hydroxy, cyano andhalo;

R₁₇ is selected from amino, halo, hydroxy, cyano, trifluoromethyl,trifluoromethoxy, C₁₋₄alkyl, and C₁₋₄alkoxy; and

each R₁₈ is independently selected from halo, hydroxy, and cyano.

In certain embodiments, compounds have structural Formula VIII:

or a salt or tautomer thereof, wherein:

R₁ is selected from halo, C₆₋₁₀aryl, C₃₋₈cycloalkyl, C₃₋₈cycloalkenyl,and a 5-9 membered heteroaryl group containing 1 to 4 heteroatoms orgroups independently selected from N, C(O), O, and S;

said aryl or heteroaryl of R₁ is optionally substituted with 1 to 5 R₁₂groups independently selected from halo, hydroxy, amino, C₁₋₄alkylamino,C₁₋₄dialkylamino, cyano, C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄hydroxyalkyl,C₁₋₄haloalkyl, C₁₋₄aminoalkyl, C₃₋₈cycloalkyl, C₃₋₈cycloalkenyl,NR₁₅C(O)R₁₃, NR₁₅C(O)OR₁₃, NR₁₃C(O)NR₁₅R₁₆, NR₁₅S(O)R₁₃, NR₁₅S(O)₂R₁₃,C(O)NR₁₅R₁₆, S(O)NR₁₅R₁₆, S(O)₂NR₁₅R₁₆, C(O)R₁₃, C(O)OR₁₃, SR₁₃,S(O)R₁₃, and S(O)₂R₁₃;

R₁₃, R₁₅, and R₁₆ are independently selected from hydrogen, C₁₋₄alkyl,and C₃₋₈cycloakyl, wherein said alkyl or cycloalkyl is optionallysubstituted by one or more substituents selected from hydroxy, cyano andhalo;

R₁₇ is selected from amino, halo, hydroxy, cyano, trifluoromethyl,trifluoromethoxy, C₁₋₄alkyl, and C₁₋₄alkoxy; and

R₁₈ is selected from halo, hydroxy, and cyano.

In certain embodiments, compounds have structural Formula IX:

or a salt or tautomer thereof, wherein:

R₁ is selected from halo, C₆₋₁₀aryl, C₃₋₈cycloalkyl, C₃₋₈cycloalkenyl,and a 5-9 membered heteroaryl group containing 1 to 4 heteroatoms orgroups independently selected from N, C(O), O, and S;

said aryl or heteroaryl of R₁ is optionally substituted with 1 to 5 R₁₂groups independently selected from halo, hydroxy, amino, C₁₋₄alkylamino,C₁₋₄dialkylamino, cyano, C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄hydroxyalkyl,C₁₋₄haloalkyl, C₁₋₄aminoalkyl, C₃₋₈cycloalkyl, C₃₋₈cycloalkenyl,NR₁₅C(O)R₁₃, NR₁₅C(O)OR₁₃, NR₁₃C(O)NR₁₅R₁₆, NR₁₅S(O)R₁₃, NR₁₅S(O)₂R₁₃,C(O)NR₁₅R₁₆, S(O)NR₁₅R₁₆, S(O)₂NR₁₅R₁₆, C(O)R₁₃, C(O)OR₁₃, SR₁₃,S(O)R₁₃, and S(O)₂R₁₃;

R₁₃, R₁₅, and R₁₆ are independently selected from hydrogen, C₁₋₄alkyl,and C₃₋₈cycloakyl, wherein said alkyl or cycloalkyl is optionallysubstituted by one or more substituents selected from hydroxy, cyano andhalo; and

R₁₇ is selected from amino, halo, hydroxy, cyano, trifluoromethyl,trifluoromethoxy, C₁₋₄alkyl, and C₁₋₄alkoxy.

In certain embodiments, compounds have structural Formula X:

or a salt or tautomer thereof, wherein:

R₁ is selected from halo, C₆₋₁₀aryl, C₃₋₈cycloalkyl, C₃₋₈cycloalkenyl,and a 5-9 membered heteroaryl group containing 1 to 4 heteroatoms orgroups independently selected from N, C(O), O, and S;

said aryl or heteroaryl of R₁ is optionally substituted with 1 to 5 R₁₂groups independently selected from halo, hydroxy, amino, C₁₋₄alkylamino,C₁₋₄dialkylamino, cyano, C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄hydroxyalkyl,C₁₋₄haloalkyl, C₁₋₄aminoalkyl, C₃₋₈cycloalkyl, C₃₋₈cycloalkenyl,NR₁₅C(O)R₁₃, NR₁₅C(O)OR₁₃, NR₁₃C(O)NR₁₅R₁₆, NR₁₅S(O)R₁₃, NR₁₅S(O)₂R₁₃,C(O)NR₁₅R₁₆, S(O)NR₁₅R₁₆, S(O)₂NR₁₅R₁₆, C(O)R₁₃, C(O)OR₁₃, SR₁₃,S(O)R₁₃, and S(O)₂R₁₃;

R₁₃, R₁₅, and R₁₆ are independently selected from hydrogen, C₁₋₄alkyl,and C₃₋₈cycloakyl, wherein said alkyl or cycloalkyl is optionallysubstituted by one or more substituents selected from hydroxy, cyano andhalo; and

R₁₇ is selected from amino, halo, hydroxy, cyano, trifluoromethyl,trifluoromethoxy, C₁₋₄alkyl, and C₁₋₄alkoxy.

In certain embodiments of any of Formulas II-X, R₁, R₆, R₇, R₁₇, and R₁₈may have the meanings set forth in any one or more of paragraphs[013]-[041].

In certain embodiments, the compound is selected from:

or a salt or tautomer thereof.

In certain embodiments, the compound is selected from:

or a salt or tautomer thereof.

In certain embodiments, R₆ is amino.

In certain embodiments, R₆ is C₁₋₄aminoalkyl.

In certain embodiments, R₆ is aminomethyl.

In certain embodiments, R₆ is methylamino.

In certain embodiments, R₇ is hydroxy.

In certain embodiments, R₇ is C₁₋₄hydroxyalkyl.

In certain embodiments, R₇ is hydroxymethyl.

In certain embodiments, R₇ is selected from cyano and amido.

In certain embodiments, R₇ is selected from cyano and —C(O)NH₂.

In certain embodiments, each R₁₂ group is independently selected fromhalo, hydroxy, amino, methylamino, dimethylamino, cyano, C₁₋₄alkyl,C₁₋₄alkoxy, C₁₋₄hydroxyalkyl, C₁₋₄haloalkyl, and C₁₋₄aminoalkyl.

In certain embodiments, each R₁₂ group is independently selected fromhalo, hydroxy, cyano, C₁₋₄alkyl, C₁₋₄alkoxy, and C₁₋₄hydroxyalkyl.

Also provided are embodiments wherein any embodiment above may becombined with any one or more of these embodiments, provided thecombination is not mutually exclusive.

As used herein, two embodiments are “mutually exclusive” when one isdefined to be something which is different than the other. For example,an embodiment wherein two groups combine to form a cycloalkyl ismutually exclusive with an embodiment in which one group is ethyl theother group is hydrogen. Similarly, an embodiment wherein one group isCH₂ is mutually exclusive with an embodiment wherein the same group isNH.

Also provided is a compound selected from the Examples disclosed herein.

The present invention also relates to a method of inhibiting at leastone PTPN11 function comprising the step of contacting PTPN11 with acompound as described herein. The cell phenotype, cell proliferation,activity of PTPN11, change in biochemical output produced by activePTPN11, expression of PTPN11, or binding of PTPN11 with a naturalbinding partner may be monitored. Such methods may be modes of treatmentof disease, biological assays, cellular assays, biochemical assays, orthe like.

Also provided herein is a method of treatment of a PTPN11-mediateddisease comprising the administration of a therapeutically effectiveamount of a compound as disclosed herein, or a salt or tautomer thereof,to a patient in need thereof.

In certain embodiments, the disease is selected from Noonan Syndrome andLeopard Syndrome.

In certain embodiments, the disease is cancer.

In certain embodiments, the cancer is selected from breast cancer, coloncancer, leukemia, or melanoma.

Also provided herein is a method of treatment of a PTP-mediated diseasecomprising the administration of a therapeutically effective amount of acompound as disclosed herein, or a salt or tautomer thereof, to apatient in need thereof.

In certain embodiments, the disease is selected from Noonan Syndrome andLeopard Syndrome.

In certain embodiments, the disease is cancer.

In certain embodiments, the cancer is selected from breast cancer, coloncancer, leukemia, or melanoma.

Also provided herein is a compound as disclosed herein for use as amedicament.

Also provided herein is a compound as disclosed herein for use as amedicament for the treatment of a PTPN11-mediated disease.

Also provided herein is a compound as disclosed herein for use as amedicament for the treatment of a PTP-mediated disease.

Also provided is the use of a compound as disclosed herein as amedicament.

Also provided is the use of a compound as disclosed herein as amedicament for the treatment of a PTPN11-mediated disease.

Also provided is a compound as disclosed herein for use in themanufacture of a medicament for the treatment of a PTPN11-mediateddisease.

Also provided is the use of a compound as disclosed herein for thetreatment of a PTPN11-mediated disease.

Also provided is the use of a compound as disclosed herein for thetreatment of a PTP-mediated disease.

Also provided herein is a method of inhibition of PTPN11 comprisingcontacting PTPN11 with a compound as disclosed herein, or a salt ortautomer thereof.

Also provided herein is a method of inhibition of PTP comprisingcontacting PTP with a compound as disclosed herein, or a salt ortautomer thereof.

Also provided herein is a method for achieving an effect in a patientcomprising the administration of a therapeutically effective amount of acompound as disclosed herein, or a salt or tautomer thereof, to apatient, wherein the effect is selected from cognition enhancement.

In certain embodiments, the PTPN11-mediated disease is selected fromNoonan Syndrome and Leopard Syndrome.

In certain embodiments, the PTPN11-mediated disease is cancer.

In certain embodiments, the PTPN11-mediated disease is selected frombreast cancer, colon cancer, leukemia, or melanoma.

Also provided is a method of modulation of a PTPN11-mediated function ina subject comprising the administration of a therapeutically effectiveamount of a compound as disclosed herein.

Also provided is a pharmaceutical composition comprising a compound asdisclosed herein, together with a pharmaceutically acceptable carrier.

In certain embodiments, the pharmaceutical composition is formulated fororal administration.

In certain embodiments, the pharmaceutical composition is formulated forparenteral administration.

In certain embodiments, the pharmaceutical composition is formulated forintravenous administration.

In certain embodiments, the pharmaceutical composition is formulated forsubcutaneous administration.

In certain embodiments, the oral pharmaceutical composition is selectedfrom a tablet and a capsule.

TERMS

As used herein, the terms below have the meanings indicated.

When ranges of values are disclosed, and the notation “from n₁ . . . ton₂” or “between n₁ . . . and n₂” is used, where n₁ and n₂ are thenumbers, then unless otherwise specified, this notation is intended toinclude the numbers themselves and the range between them. This rangemay be integral or continuous between and including the end values. Byway of example, the range “from 2 to 6 carbons” is intended to includetwo, three, four, five, and six carbons, since carbons come in integerunits. Compare, by way of example, the range “from 1 to 3 (micromolar),”which is intended to include 1 μM, 3 μM, and everything in between toany number of significant figures (e.g., 1.255 μM, 2.1 μM, 2.9999 μM,etc.).

The term “about,” as used herein, is intended to qualify the numericalvalues which it modifies, denoting such a value as variable within amargin of error. When no particular margin of error, such as a standarddeviation to a mean value given in a chart or table of data, is recited,the term “about” should be understood to mean that range which wouldencompass the recited value and the range which would be included byrounding up or down to that figure as well, taking into accountsignificant figures.

The term “acyl,” as used herein, alone or in combination, refers to acarbonyl attached to an alkenyl, alkyl, aryl, cycloalkyl, heteroaryl,heterocycle, or any other moiety were the atom attached to the carbonylis carbon. An “acetyl” group refers to a —C(O)CH₃ group. An“alkylcarbonyl” or “alkanoyl” group refers to an alkyl group attached tothe parent molecular moiety through a carbonyl group. Examples of suchgroups include methylcarbonyl and ethylcarbonyl. Examples of acyl groupsinclude formyl, alkanoyl and aroyl.

The term “alkenyl,” as used herein, alone or in combination, refers to astraight-chain or branched-chain hydrocarbon radical having one or moredouble bonds and containing from 2 to 20 carbon atoms. In certainembodiments, said alkenyl will comprise from 2 to 6 carbon atoms. Theterm “alkenylene” refers to a carbon-carbon double bond system attachedat two or more positions such as ethenylene [(—CH═CH—), (—C::C—)].Examples of suitable alkenyl radicals include ethenyl, propenyl,2-methylpropenyl, 1,4-butadienyl and the like. Unless otherwisespecified, the term “alkenyl” may include “alkenylene” groups.

The term “alkoxy,” as used herein, alone or in combination, refers to analkyl ether radical, wherein the term alkyl is as defined below.Examples of suitable alkyl ether radicals include methoxy, ethoxy,n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy,and the like.

The term “alkyl,” as used herein, alone or in combination, refers to astraight-chain or branched-chain alkyl radical containing from 1 to 20carbon atoms. In certain embodiments, said alkyl will comprise from 1 to10 carbon atoms. In further embodiments, said alkyl will comprise from 1to 8 carbon atoms. Alkyl groups are optionally substituted as definedherein. Examples of alkyl radicals include methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl,hexyl, octyl, noyl and the like. The term “alkylene,” as used herein,alone or in combination, refers to a saturated aliphatic group derivedfrom a straight or branched chain saturated hydrocarbon attached at twoor more positions, such as methylene (—CH₂—). Unless otherwisespecified, the term “alkyl” may include “alkylene” groups.

The term “alkylamino,” as used herein, alone or in combination, refersto an alkyl group attached to the parent molecular moiety through anamino group. Suitable alkylamino groups may be mono- or dialkylated,forming groups such as, for example, N-methylamino, N-ethylamino,N,N-dimethylamino, N,N-ethylmethylamino and the like.

The term “alkylthio,” as used herein, alone or in combination, refers toan alkyl thioether (R—S—) radical wherein the term alkyl is as definedabove and wherein the sulfur may be singly or doubly oxidized. Examplesof suitable alkyl thioether radicals include methylthio, ethylthio,n-propylthio, isopropylthio, n-butylthio, iso-butylthio, sec-butylthio,tert-butylthio, methanesulfonyl, ethanesulfinyl, and the like.

The terms “amido” and “carbamoyl,” as used herein, alone or incombination, refer to an amino group as described below attached to theparent molecular moiety through a carbonyl group, or vice versa. Theterm “C-amido” as used herein, alone or in combination, refers to a—C(O)N(RR′) group with R and R′ as defined herein or as defined by thespecifically enumerated “R” groups designated. The term “N-amido” asused herein, alone or in combination, refers to a RC(O)N(R′)— group,with R and R′ as defined herein or as defined by the specificallyenumerated “R” groups designated. The term “acylamino” as used herein,alone or in combination, embraces an acyl group attached to the parentmoiety through an amino group. An example of an “acylamino” group isacetylamino (CH₃C(O)NH—).

The term “amino,” as used herein, alone or in combination, refers to—NRR′, wherein R and R′ are independently selected from hydrogen, alkyl,acyl, heteroalkyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl,any of which may themselves be optionally substituted. Additionally, Rand R′ may combine to form heterocycloalkyl, either of which isoptionally substituted.

The term “aryl,” as used herein, alone or in combination, means acarbocyclic aromatic system containing one, two or three rings whereinsuch polycyclic ring systems are fused together. The term “aryl”embraces aromatic groups such as phenyl, naphthyl, anthracenyl, andphenanthryl.

The term “arylalkenyl” or “aralkenyl,” as used herein, alone or incombination, refers to an aryl group attached to the parent molecularmoiety through an alkenyl group.

The term “arylalkoxy” or “aralkoxy,” as used herein, alone or incombination, refers to an aryl group attached to the parent molecularmoiety through an alkoxy group.

The term “arylalkyl” or “aralkyl,” as used herein, alone or incombination, refers to an aryl group attached to the parent molecularmoiety through an alkyl group.

The term aryloxy as used herein, alone or in combination, refers to anaryl group attached to the parent molecular moiety through an oxy.

The term “carbamate,” as used herein, alone or in combination, refers toan ester of carbamic acid (—NHCOO—) which may be attached to the parentmolecular moiety from either the nitrogen or acid end, and which isoptionally substituted as defined herein.

The term “O-carbamyl” as used herein, alone or in combination, refers toa —OC(O)NRR′, group—with R and R′ as defined herein.

The term “N-carbamyl” as used herein, alone or in combination, refers toa ROC(O)NR′— group, with R and R′ as defined herein.

The term “carbonyl,” as used herein, when alone includes formyl [—C(O)H]and in combination is a —C(O)— group.

The term “carboxyl” or “carboxy,” as used herein, refers to —C(O)OH orthe corresponding “carboxylate” anion, such as is in a carboxylic acidsalt. An “O-carboxy” group refers to a RC(O)O— group, where R is asdefined herein. A “C-carboxy” group refers to a —C(O)OR groups where Ris as defined herein.

The term “cyano,” as used herein, alone or in combination, refers to—CN.

The term “cycloalkyl,” or, alternatively, “carbocycle,” as used herein,alone or in combination, refers to a saturated or partially saturatedmonocyclic, bicyclic or tricyclic alkyl group wherein each cyclic moietycontains from 3 to 12 carbon atom ring members and which may optionallybe a benzo fused ring system which is optionally substituted as definedherein. In certain embodiments, said cycloalkyl will comprise from 5 to7 carbon atoms. Examples of such cycloalkyl groups include cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, tetrahydronapthyl,indanyl, octahydronaphthyl, 2,3-dihydro-1H-indenyl, adamantyl and thelike. “Bicyclic” and “tricyclic” as used herein are intended to includeboth fused ring systems, such as decahydronaphthalene,octahydronaphthalene as well as the multicyclic (multicentered)saturated or partially unsaturated type. The latter type of isomer isexemplified in general by, bicyclo[1,1,1]pentane, camphor, adamantane,and bicyclo[3,2,1]octane.

The term “ester,” as used herein, alone or in combination, refers to acarboxy group bridging two moieties linked at carbon atoms.

The term “ether,” as used herein, alone or in combination, refers to anoxy group bridging two moieties linked at carbon atoms.

The term “halo,” or “halogen,” as used herein, alone or in combination,refers to fluorine, chlorine, bromine, or iodine.

The term “haloalkoxy,” as used herein, alone or in combination, refersto a haloalkyl group attached to the parent molecular moiety through anoxygen atom.

The term “haloalkyl,” as used herein, alone or in combination, refers toan alkyl radical having the meaning as defined above wherein one or morehydrogens are replaced with a halogen. Specifically embraced aremonohaloalkyl, dihaloalkyl and polyhaloalkyl radicals. A monohaloalkylradical, for one example, may have an iodo, bromo, chloro, or fluoroatom within the radical. Dihalo and polyhaloalkyl radicals may have twoor more of the same halo atoms or a combination of different haloradicals. Examples of haloalkyl radicals include fluoromethyl,difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl,trichloromethyl, pentafluoroethyl, heptafluoropropyl,difluorochloromethyl, dichlorofluoromethyl, difluoroethyl,difluoropropyl, dichloroethyl and dichloropropyl. “Haloalkylene” refersto a haloalkyl group attached at two or more positions. Examples includefluoromethylene (—CFH—), difluoromethylene (—CF₂—), chloromethylene(—CHCl—) and the like.

The term “heteroalkyl,” as used herein, alone or in combination, refersto a stable straight or branched chain, or combinations thereof, fullysaturated or containing from 1 to 3 degrees of unsaturation, consistingof the stated number of carbon atoms and from one to three heteroatomsselected from N, O, and S, and wherein the N and S atoms may optionallybe oxidized and the N heteroatom may optionally be quaternized. Theheteroatom(s) may be placed at any interior position of the heteroalkylgroup. Up to two heteroatoms may be consecutive, such as, for example,—CH₂—NH—OCH₃.

The term “heteroaryl,” as used herein, alone or in combination, refersto a 3 to 15 membered unsaturated heteromonocyclic ring, or a fusedmonocyclic, bicyclic, or tricyclic ring system in which at least one ofthe fused rings is aromatic, which contains at least one atom selectedfrom N, O, and S. In certain embodiments, said heteroaryl will comprisefrom 1 to 4 heteroatoms as ring members. In further embodiments, saidheteroaryl will comprise from 1 to 2 heteroatoms as ring members. Incertain embodiments, said heteroaryl will comprise from 5 to 7 atoms.The term also embraces fused polycyclic groups wherein heterocyclicrings are fused with aryl rings, wherein heteroaryl rings are fused withother heteroaryl rings, wherein heteroaryl rings are fused withheterocycloalkyl rings, or wherein heteroaryl rings are fused withcycloalkyl rings. Examples of heteroaryl groups include pyrrolyl,pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl,pyridazinyl, triazolyl, pyranyl, furyl, thienyl, oxazolyl, isoxazolyl,oxadiazolyl, thiazolyl, thiadiazolyl, isothiazolyl, indolyl, isoindolyl,indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, quinoxalinyl,quinazolinyl, indazolyl, benzotriazolyl, benzodioxolyl, benzopyranyl,benzoxazolyl, benzoxadiazolyl, benzothiazolyl, benzothiadiazolyl,benzofuryl, benzothienyl, chromonyl, coumarinyl, benzopyranyl,tetrahydroquinolinyl, tetrazolopyridazinyl, tetrahydroisoquinolinyl,thienopyridinyl, furopyridinyl, pyrrolopyridinyl and the like. Exemplarytricyclic heterocyclic groups include carbazolyl, benzidolyl,phenanthrolinyl, dibenzofuranyl, acridinyl, phenanthridinyl, xanthenyland the like.

The terms “heterocycloalkyl” and, interchangeably, “heterocycle,” asused herein, alone or in combination, each refer to a saturated,partially unsaturated, or fully unsaturated (but nonaromatic)monocyclic, bicyclic, or tricyclic heterocyclic group containing atleast one heteroatom as a ring member, wherein each said heteroatom maybe independently selected from nitrogen, oxygen, and sulfur. In certainembodiments, said heterocycloalkyl will comprise from 1 to 4 heteroatomsas ring members. In further embodiments, said heterocycloalkyl willcomprise from 1 to 2 heteroatoms as ring members. In certainembodiments, said heterocycloalkyl will comprise from 3 to 8 ringmembers in each ring. In further embodiments, said heterocycloalkyl willcomprise from 3 to 7 ring members in each ring. In yet furtherembodiments, said heterocycloalkyl will comprise from 5 to 6 ringmembers in each ring. “Heterocycloalkyl” and “heterocycle” are intendedto include sulfones, sulfoxides, N-oxides of tertiary nitrogen ringmembers, and carbocyclic fused and benzo fused ring systems;additionally, both terms also include systems where a heterocycle ringis fused to an aryl group, as defined herein, or an additionalheterocycle group. Examples of heterocycle groups include aziridinyl,azetidinyl, 1,3-benzodioxolyl, dihydroisoindolyl, dihydroisoquinolinyl,dihydrocinnolinyl, dihydrobenzodioxinyl,dihydro[1,3]oxazolo[4,5-b]pyridinyl, benzothiazolyl, dihydroindolyl,dihydropyridinyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3-dioxolanyl,isoindolinyl, morpholinyl, piperazinyl, pyrrolidinyl,tetrahydropyridinyl, piperidinyl, thiomorpholinyl, and the like. Theheterocycle groups are optionally substituted unless specificallyprohibited.

The term “hydrazinyl” as used herein, alone or in combination, refers totwo amino groups joined by a single bond, i.e., —N—N—.

The term “hydroxy,” as used herein, alone or in combination, refers to—OH.

The term “hydroxyalkyl,” as used herein, alone or in combination, refersto a hydroxy group attached to the parent molecular moiety through analkyl group.

The term “iminohydroxy,” as used herein, alone or in combination, refersto ═N(OH) and ═N—O—.

The term “lower amino,” as used herein, alone or in combination, refersto —NRR′, wherein R and R′ are independently selected from hydrogen andlower alkyl, either of which is optionally substituted.

The term “mercaptyl” as used herein, alone or in combination, refers toan RS— group, where R is as defined herein.

The term “nitro,” as used herein, alone or in combination, refers to—NO₂.

The terms “oxy” or “oxa,” as used herein, alone or in combination, referto —O—.

The term “oxo,” as used herein, alone or in combination, refers to ═O.

The term “perhaloalkoxy” refers to an alkoxy group where all of thehydrogen atoms are replaced by halogen atoms.

The term “perhaloalkyl” as used herein, alone or in combination, refersto an alkyl group where all of the hydrogen atoms are replaced byhalogen atoms.

The term “ring,” or equivalently, “cycle,” as used herein, in referenceto a chemical structure or portion thereof, means a group in which everyatom is a member of a common cyclic structure. A ring can be saturatedor unsaturated, including aromatic, unless otherwise provided, and mayhave between 3 and 9 members. If the ring is a heterocycle, it maycontain between 1 and 4 heteroatoms or heteroatom-comprising groupsselected from B, N, O, S, C(O), S(O)m. Unless specifically prohibited, aring is optionally substituted.

The terms “sulfonate,” “sulfonic acid,” and “sulfonic,” as used herein,alone or in combination, refer to the —SO₃H group and its anion as thesulfonic acid is used in salt formation.

The term “sulfanyl,” as used herein, alone or in combination, refers to—S—.

The term “sulfinyl,” as used herein, alone or in combination, refers to—S(O)—.

The term “sulfonyl,” as used herein, alone or in combination, refers to—S(O)₂—.

The term “N-sulfonamido” refers to a RS(═O)₂NR′— group with R and R′ asdefined herein.

The term “S-sulfonamido” refers to a —S(═O)₂NRR′, group, with R and R′as defined herein.

The term “tautomer”, as use herein, alone or in combination, refers toone of two or more isomers that rapidly interconvert. Generally, thisinterconversion is sufficiently fast so that an individual tautomer isnot isolated in the absence of another tautomer. The ratio of the amountof tautomers can be dependent on solvent composition, ionic strength,and pH, as well as other solution parameters. The ratio of the amount oftautomers can be different in a particular solution and in themicroenvironment of a biomolecular binding site in said solution.Examples of tautomers that are well known in the art include keto/enol,enamine/imine, and lactam/lactim tautomers. Examples of tautomers thatare well known in the art also include 2-hydroxypyridine/2(1H)-pyridoneand 2-aminopyridine/2(1H)-iminopyridone tautomers.

The terms “thia” and “thio,” as used herein, alone or in combination,refer to a —S— group or an ether wherein the oxygen is replaced withsulfur. The oxidized derivatives of the thio group, namely sulfinyl andsulfonyl, are included in the definition of thia and thio.

The term “thiol,” as used herein, alone or in combination, refers to an—SH group.

The term “thiocarbonyl,” as used herein, when alone includes thioformyl—C(S)H and in combination is a —C(S)— group.

The term “N-thiocarbamyl” refers to an ROC(S)NR′— group, with R and R′as defined herein.

The term “O-thiocarbamyl” refers to a —OC(S)NRR′, group with R and R′ asdefined herein.

The term “thiocyanato” refers to a —CNS group.

Any definition herein may be used in combination with any otherdefinition to describe a composite structural group. By convention, thetrailing element of any such definition is that which attaches to theparent moiety. For example, the composite group alkylamido wouldrepresent an alkyl group attached to the parent molecule through anamido group, and the term alkoxyalkyl would represent an alkoxy groupattached to the parent molecule through an alkyl group.

When a group is defined to be “null,” what is meant is that said groupis absent.

The term “optionally substituted” means the anteceding group may besubstituted or unsubstituted. When substituted, the substituents of an“optionally substituted” group may include, without limitation, one ormore substituents independently selected from the following groups or aparticular designated set of groups, alone or in combination: loweralkyl, lower alkenyl, lower alkynyl, lower alkanoyl, lower heteroalkyl,lower haloalkyl, lower haloalkenyl, lower haloalkynyl, lowerperhaloalkyl, lower perhaloalkoxy, phenyl, aryl, aryloxy, lower alkoxy,lower haloalkoxy, oxo, lower acyloxy, carbonyl, carboxyl, loweralkylcarbonyl, lower carboxyester, lower carboxamido, cyano, hydrogen,halogen, hydroxy, amino, lower alkylamino, arylamino, amido, nitro,thiol, lower alkylthio, lower haloalkylthio, lower perhaloalkylthio,arylthio, sulfonate, sulfonic acid, trisubstituted silyl, N₃, SH, SCH₃,C(O)CH₃, CO₂CH₃, CO₂H, pyridinyl, thiophene, furanyl, lower carbamate,and lower urea. Where structurally feasible, two substituents may bejoined together to form a fused five-, six-, or seven-memberedcarbocyclic or heterocyclic ring consisting of zero to threeheteroatoms, for example forming methylenedioxy or ethylenedioxy. Anoptionally substituted group may be unsubstituted (e.g., —CH₂CH₃), fullysubstituted (e.g., —CF₂CF₃), monosubstituted (e.g., —CH₂CH₂F) orsubstituted at a level anywhere in-between fully substituted andmonosubstituted (e.g., —CH₂CF₃). Where substituents are recited withoutqualification as to substitution, both substituted and unsubstitutedforms are encompassed. Where a substituent is qualified as“substituted,” the substituted form is specifically intended.Additionally, different sets of optional substituents to a particularmoiety may be defined as needed; in these cases, the optionalsubstitution will be as defined, often immediately following the phrase,“optionally substituted with.”

The term R or the term R′, appearing by itself and without a numberdesignation, unless otherwise defined, refers to a moiety selected fromhydrogen, alkyl, cycloalkyl, heteroalkyl, aryl, heteroaryl andheterocycloalkyl, any of which is optionally substituted. Such R and R′groups should be understood to be optionally substituted as definedherein. Whether an R group has a number designation or not, every Rgroup, including R, R′ and R^(n) where n=(1, 2, 3, . . . n), everysubstituent, and every term should be understood to be independent ofevery other in terms of selection from a group. Should any variable,substituent, or term (e.g. aryl, heterocycle, R, etc.) occur more thanone time in a formula or generic structure, its definition at eachoccurrence is independent of the definition at every other occurrence.Those of skill in the art will further recognize that certain groups maybe attached to a parent molecule or may occupy a position in a chain ofelements from either end as written. For example, an unsymmetrical groupsuch as —C(O)N(R)— may be attached to the parent moiety at either thecarbon or the nitrogen.

Asymmetric centers exist in the compounds disclosed herein. Thesecenters are designated by the symbols “R” or “S,” depending on theconfiguration of substituents around the chiral carbon atom. It shouldbe understood that the invention encompasses all stereochemical isomericforms, including diastereomeric, enantiomeric, and epimeric forms, aswell as d-isomers and l-isomers, and mixtures thereof. Individualstereoisomers of compounds can be prepared synthetically fromcommercially available starting materials which contain chiral centersor by preparation of mixtures of enantiomeric products followed byseparation such as conversion to a mixture of diastereomers followed byseparation or recrystallization, chromatographic techniques, directseparation of enantiomers on chiral chromatographic columns, or anyother appropriate method known in the art. Starting compounds ofparticular stereochemistry are either commercially available or can bemade and resolved by techniques known in the art. Additionally, thecompounds disclosed herein may exist as geometric isomers. The presentinvention includes all cis, trans, syn, anti, entgegen (E), and zusammen(Z) isomers as well as the appropriate mixtures thereof. Additionally,compounds may exist as tautomers; all tautomeric isomers are provided bythis invention. Additionally, the compounds disclosed herein can existin unsolvated as well as solvated forms with pharmaceutically acceptablesolvents such as water, ethanol, and the like. In general, the solvatedforms are considered equivalent to the unsolvated forms.

The term “bond” refers to a covalent linkage between two atoms, or twomoieties when the atoms joined by the bond are considered to be part oflarger substructure. A bond may be single, double, or triple unlessotherwise specified. A dashed line between two atoms in a drawing of amolecule indicates that an additional bond may be present or absent atthat position.

The term “disease” as used herein is intended to be generallysynonymous, and is used interchangeably with, the terms “disorder,”“syndrome,” and “condition” (as in medical condition), in that allreflect an abnormal condition of the human or animal body or of one ofits parts that impairs normal functioning, is typically manifested bydistinguishing signs and symptoms, and causes the human or animal tohave a reduced duration or quality of life.

The term “combination therapy” means the administration of two or moretherapeutic agents to treat a therapeutic condition or disorderdescribed in the present disclosure. Such administration encompassesco-administration of these therapeutic agents in a substantiallysimultaneous manner, such as in a single capsule having a fixed ratio ofactive ingredients or in multiple, separate capsules for each activeingredient. In addition, such administration also encompasses use ofeach type of therapeutic agent in a sequential manner. In either case,the treatment regimen will provide beneficial effects of the drugcombination in treating the conditions or disorders described herein.

“PTPN11 inhibitor” is used herein to refer to a compound that exhibitsan IC₅₀ with respect to PTPN11 activity of no more than about 100 μM andmore typically not more than about 50 μM, as measured in the PTPN11assay described generally herein. “IC₅₀” is that concentration ofinhibitor which reduces the activity of an enzyme (e.g., PTPN11) tohalf-maximal level. Certain compounds disclosed herein have beendiscovered to exhibit inhibition against PTPN11. In certain embodiments,compounds will exhibit an IC₅₀ with respect to PTPN11 of no more thanabout 50 μM; in further embodiments, compounds will exhibit an IC₅₀ withrespect to PTPN11 of no more than about 10 μM; in yet furtherembodiments, compounds will exhibit an IC₅₀ with respect to PTPN11 ofnot more than about 1 μM; in yet further embodiments, compounds willexhibit an IC₅₀ with respect to PTPN11 of not more than about 200 nM, asmeasured in the PTPN11 assay described herein.

The phrase “therapeutically effective” is intended to qualify the amountof active ingredients used in the treatment of a disease or disorder oron the effecting of a clinical endpoint.

The term “therapeutically acceptable” refers to those compounds (orsalts, prodrugs, tautomers, zwitterionic forms, etc.) which are suitablefor use in contact with the tissues of patients without undue toxicity,irritation, and allergic response, are commensurate with a reasonablebenefit/risk ratio, and are effective for their intended use.

As used herein, reference to “treatment” of a patient is intended toinclude prophylaxis. Treatment may also be preemptive in nature, i.e.,it may include prevention of disease. Prevention of a disease mayinvolve complete protection from disease, for example as in the case ofprevention of infection with a pathogen, or may involve prevention ofdisease progression. For example, prevention of a disease may not meancomplete foreclosure of any effect related to the diseases at any level,but instead may mean prevention of the symptoms of a disease to aclinically significant or detectable level. Prevention of diseases mayalso mean prevention of progression of a disease to a later stage of thedisease.

The term “patient” is generally synonymous with the term “subject” andincludes all mammals including humans. Examples of patients includehumans, livestock such as cows, goats, sheep, pigs, and rabbits, andcompanion animals such as dogs, cats, rabbits, and horses. Preferably,the patient is a human.

The term “prodrug” refers to a compound that is made more active invivo. Certain compounds disclosed herein may also exist as prodrugs.Prodrugs of the compounds described herein are structurally modifiedforms of the compound that readily undergo chemical changes underphysiological conditions to provide the compound. Additionally, prodrugscan be converted to the compound by chemical or biochemical methods inan ex vivo environment. For example, prodrugs can be slowly converted toa compound when placed in a transdermal patch reservoir with a suitableenzyme or chemical reagent. Prodrugs are often useful because, in somesituations, they may be easier to administer than the compound, orparent drug. They may, for instance, be bioavailable by oraladministration whereas the parent drug is not. The prodrug may also haveimproved solubility in pharmaceutical compositions over the parent drug.A wide variety of prodrug derivatives are known in the art, such asthose that rely on hydrolytic cleavage or oxidative activation of theprodrug. An example, without limitation, of a prodrug would be acompound which is administered as an ester (the “prodrug”), but then ismetabolically hydrolyzed to the carboxylic acid, the active entity.Additional examples include peptidyl derivatives of a compound.

The compounds disclosed herein can exist as therapeutically acceptablesalts. The present invention includes compounds listed above in the formof salts, including acid addition salts. Suitable salts include thoseformed with both organic and inorganic acids. Such acid addition saltswill normally be pharmaceutically acceptable. However, salts ofnon-pharmaceutically acceptable salts may be of utility in thepreparation and purification of the compound in question. Basic additionsalts may also be formed and be pharmaceutically acceptable.

The term “therapeutically acceptable salt,” as used herein, representssalts or zwitterionic forms of the compounds disclosed herein which arewater or oil-soluble or dispersible and therapeutically acceptable asdefined herein. The salts can be prepared during the final isolation andpurification of the compounds or separately by reacting the appropriatecompound in the form of the free base with a suitable acid.Representative acid addition salts include acetate, adipate, alginate,L-ascorbate, aspartate, benzoate, benzenesulfonate (besylate),bisulfate, butyrate, camphorate, camphorsulfonate, citrate, digluconate,formate, fumarate, gentisate, glutarate, glycerophosphate, glycolate,hemisulfate, heptanoate, hexanoate, hippurate, hydrochloride,hydrobromide, hydroiodide, 2-hydroxyethansulfonate (isethionate),lactate, maleate, malonate, DL-mandelate, mesitylenesulfonate,methanesulfonate, naphthylenesulfonate, nicotinate,2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate,3-phenylproprionate, phosphonate, picrate, pivalate, propionate,pyroglutamate, succinate, sulfonate, tartrate, L-tartrate,trichloroacetate, trifluoroacetate, phosphate, glutamate, bicarbonate,para-toluenesulfonate (p-tosylate), and undecanoate. Also, basic groupsin the compounds disclosed herein can be quaternized with methyl, ethyl,propyl, and butyl chlorides, bromides, and iodides; dimethyl, diethyl,dibutyl, and diamyl sulfates; decyl, lauryl, myristyl, and sterylchlorides, bromides, and iodides; and benzyl and phenethyl bromides.Examples of acids which can be employed to form therapeuticallyacceptable addition salts include inorganic acids such as hydrochloric,hydrobromic, sulfuric, and phosphoric, and organic acids such as oxalic,maleic, succinic, and citric. Salts can also be formed by coordinationof the compounds with an alkali metal or alkaline earth ion. Hence, thepresent invention contemplates sodium, potassium, magnesium, and calciumsalts of the compounds disclosed herein, and the like.

Basic addition salts can be prepared during the final isolation andpurification of the compounds by reacting a carboxy group with asuitable base such as the hydroxide, carbonate, or bicarbonate of ametal cation or with ammonia or an organic primary, secondary, ortertiary amine. The cations of therapeutically acceptable salts includelithium, sodium, potassium, calcium, magnesium, and aluminum, as well asnontoxic quaternary amine cations such as ammonium, tetramethylammonium,tetraethylammonium, methylamine, dimethylamine, trimethylamine,triethylamine, diethylamine, ethylamine, tributylamine, pyridine,N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine,dicyclohexylamine, procaine, dibenzylamine, N,N-dibenzylphenethylamine,1-ephenamine, and N,N′-dibenzylethylenediamine. Other representativeorganic amines useful for the formation of base addition salts includeethylenediamine, ethanolamine, diethanolamine, piperidine, andpiperazine.

A salt of a compound can be made by reacting the appropriate compound inthe form of the free base with the appropriate acid.

While it may be possible for the compounds of the subject invention tobe administered as the raw chemical, it is also possible to present themas a pharmaceutical formulation. Accordingly, provided herein arepharmaceutical formulations which comprise one or more of certaincompounds disclosed herein, or one or more pharmaceutically acceptablesalts, esters, prodrugs, amides, or solvates thereof, together with oneor more pharmaceutically acceptable carriers thereof and optionally oneor more other therapeutic ingredients. The carrier(s) must be“acceptable” in the sense of being compatible with the other ingredientsof the formulation and not deleterious to the recipient thereof. Properformulation is dependent upon the route of administration selected. Anyof the well-known techniques, carriers, and excipients may be used assuitable and as understood in the art. The pharmaceutical compositionsdisclosed herein may be manufactured in any manner known in the art,e.g., by means of conventional mixing, dissolving, granulating,dragee-making, levigating, emulsifying, encapsulating, entrapping orcompression processes.

The formulations include those suitable for oral, parenteral (includingsubcutaneous, intradermal, intramuscular, intravenous, intraarticular,and intramedullary), intraperitoneal, transmucosal, transdermal, rectaland topical (including dermal, buccal, sublingual and intraocular)administration although the most suitable route may depend upon forexample the condition and disorder of the recipient. The formulationsmay conveniently be presented in unit dosage form and may be prepared byany of the methods well known in the art of pharmacy. Typically, thesemethods include the step of bringing into association a compound of thesubject invention or a pharmaceutically acceptable salt, ester, amide,prodrug or solvate thereof (“active ingredient”) with the carrier whichconstitutes one or more accessory ingredients. In general, theformulations are prepared by uniformly and intimately bringing intoassociation the active ingredient with liquid carriers or finely dividedsolid carriers or both and then, if necessary, shaping the product intothe desired formulation.

Formulations of the compounds disclosed herein suitable for oraladministration may be presented as discrete units such as capsules,cachets or tablets each containing a predetermined amount of the activeingredient; as a powder or granules; as a solution or a suspension in anaqueous liquid or a non-aqueous liquid; or as an oil-in-water liquidemulsion or a water-in-oil liquid emulsion. The active ingredient mayalso be presented as a bolus, electuary or paste.

Pharmaceutical preparations which can be used orally include tablets,push-fit capsules made of gelatin, as well as soft, sealed capsules madeof gelatin and a plasticizer, such as glycerol or sorbitol. Tablets maybe made by compression or molding, optionally with one or more accessoryingredients. Compressed tablets may be prepared by compressing in asuitable machine the active ingredient in a free-flowing form such as apowder or granules, optionally mixed with binders, inert diluents, orlubricating, surface active or dispersing agents. Molded tablets may bemade by molding in a suitable machine a mixture of the powdered compoundmoistened with an inert liquid diluent. The tablets may optionally becoated or scored and may be formulated so as to provide slow orcontrolled release of the active ingredient therein. All formulationsfor oral administration should be in dosages suitable for suchadministration. The push-fit capsules can contain the active ingredientsin admixture with filler such as lactose, binders such as starches,and/or lubricants such as talc or magnesium stearate and, optionally,stabilizers. In soft capsules, the active compounds may be dissolved orsuspended in suitable liquids, such as fatty oils, liquid paraffin, orliquid polyethylene glycols. In addition, stabilizers may be added.Dragee cores are provided with suitable coatings. For this purpose,concentrated sugar solutions may be used, which may optionally containgum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethyleneglycol, and/or titanium dioxide, lacquer solutions, and suitable organicsolvents or solvent mixtures. Dyestuffs or pigments may be added to thetablets or dragee coatings for identification or to characterizedifferent combinations of active compound doses.

The compounds may be formulated for parenteral administration byinjection, e.g., by bolus injection or continuous infusion. Formulationsfor injection may be presented in unit dosage form, e.g., in ampoules orin multi-dose containers, with an added preservative. The compositionsmay take such forms as suspensions, solutions or emulsions in oily oraqueous vehicles, and may contain formulatory agents such as suspending,stabilizing and/or dispersing agents. The formulations may be presentedin unit-dose or multi-dose containers, for example sealed ampoules andvials, and may be stored in powder form or in a freeze-dried(lyophilized) condition requiring only the addition of the sterileliquid carrier, for example, saline or sterile pyrogen-free water,immediately prior to use. Extemporaneous injection solutions andsuspensions may be prepared from sterile powders, granules and tabletsof the kind previously described.

Formulations for parenteral administration include aqueous andnon-aqueous (oily) sterile injection solutions of the active compoundswhich may contain antioxidants, buffers, bacteriostats and solutes whichrender the formulation isotonic with the blood of the intendedrecipient; and aqueous and non-aqueous sterile suspensions which mayinclude suspending agents and thickening agents. Suitable lipophilicsolvents or vehicles include fatty oils such as sesame oil, or syntheticfatty acid esters, such as ethyl oleate or triglycerides, or liposomes.Aqueous injection suspensions may contain substances which increase theviscosity of the suspension, such as sodium carboxymethyl cellulose,sorbitol, or dextran. Optionally, the suspension may also containsuitable stabilizers or agents which increase the solubility of thecompounds to allow for the preparation of highly concentrated solutions.

In addition to the formulations described previously, the compounds mayalso be formulated as a depot preparation. Such long acting formulationsmay be administered by implantation (for example subcutaneously orintramuscularly) or by intramuscular injection. Thus, for example, thecompounds may be formulated with suitable polymeric or hydrophobicmaterials (for example as an emulsion in an acceptable oil) or ionexchange resins, or as sparingly soluble derivatives, for example, as asparingly soluble salt.

For buccal or sublingual administration, the compositions may take theform of tablets, lozenges, pastilles, or gels formulated in conventionalmanner. Such compositions may comprise the active ingredient in aflavored basis such as sucrose and acacia or tragacanth.

The compounds may also be formulated in rectal compositions such assuppositories or retention enemas, e.g., containing conventionalsuppository bases such as cocoa butter, polyethylene glycol, or otherglycerides.

Certain compounds disclosed herein may be administered topically, thatis by non-systemic administration. This includes the application of acompound disclosed herein externally to the epidermis or the buccalcavity and the instillation of such a compound into the ear, eye andnose, such that the compound does not significantly enter the bloodstream. In contrast, systemic administration refers to oral,intravenous, intraperitoneal and intramuscular administration.

Formulations suitable for topical administration include liquid orsemi-liquid preparations suitable for penetration through the skin tothe site of inflammation such as gels, liniments, lotions, creams,ointments or pastes, and drops suitable for administration to the eye,ear or nose. The active ingredient for topical administration maycomprise, for example, from 0.001% to 10% w/w (by weight) of theformulation. In certain embodiments, the active ingredient may compriseas much as 10% w/w. In other embodiments, it may comprise less than 5%w/w. In certain embodiments, the active ingredient may comprise from 2%w/w to 5% w/w. In other embodiments, it may comprise from 0.1% to 1% w/wof the formulation.

For administration by inhalation, compounds may be convenientlydelivered from an insufflator, nebulizer pressurized packs or otherconvenient means of delivering an aerosol spray. Pressurized packs maycomprise a suitable propellant such as dichlorodifluoromethane,trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide orother suitable gas. In the case of a pressurized aerosol, the dosageunit may be determined by providing a valve to deliver a metered amount.Alternatively, for administration by inhalation or insufflation, thecompounds according to the invention may take the form of a dry powdercomposition, for example a powder mix of the compound and a suitablepowder base such as lactose or starch. The powder composition may bepresented in unit dosage form, in for example, capsules, cartridges,gelatin or blister packs from which the powder may be administered withthe aid of an inhalator or insufflator.

Preferred unit dosage formulations are those containing an effectivedose, as herein below recited, or an appropriate fraction thereof, ofthe active ingredient.

It should be understood that in addition to the ingredients particularlymentioned above, the formulations described above may include otheragents conventional in the art having regard to the type of formulationin question, for example those suitable for oral administration mayinclude flavoring agents.

Compounds may be administered orally or via injection at a dose of from0.1 to 500 mg/kg per day. The dose range for adult humans is generallyfrom 5 mg to 2 g/day. Tablets or other forms of presentation provided indiscrete units may conveniently contain an amount of one or morecompounds which is effective at such dosage or as a multiple of thesame, for instance, units containing 5 mg to 500 mg, usually around 10mg to 200 mg.

The amount of active ingredient that may be combined with the carriermaterials to produce a single dosage form will vary depending upon thehost treated and the particular mode of administration.

The compounds can be administered in various modes, e.g. orally,topically, or by injection. The precise amount of compound administeredto a patient will be the responsibility of the attendant physician. Thespecific dose level for any particular patient will depend upon avariety of factors including the activity of the specific compoundemployed, the age, body weight, general health, sex, diets, time ofadministration, route of administration, rate of excretion, drugcombination, the precise disorder being treated, and the severity of theindication or condition being treated. Also, the route of administrationmay vary depending on the condition and its severity.

In certain instances, it may be appropriate to administer at least oneof the compounds described herein (or a pharmaceutically acceptablesalt, ester, tautomer, or prodrug thereof) in combination with anothertherapeutic agent. By way of example only, if one of the side effectsexperienced by a patient upon receiving one of the compounds herein ishypertension, then it may be appropriate to administer ananti-hypertensive agent in combination with the initial therapeuticagent. Or, by way of example only, the therapeutic effectiveness of oneof the compounds described herein may be enhanced by administration ofan adjuvant (i.e., by itself the adjuvant may only have minimaltherapeutic benefit, but in combination with another therapeutic agent,the overall therapeutic benefit to the patient is enhanced). Or, by wayof example only, the benefit of experienced by a patient may beincreased by administering one of the compounds described herein withanother therapeutic agent (which also includes a therapeutic regimen)that also has therapeutic benefit. By way of example only, in atreatment for diabetes involving administration of one of the compoundsdescribed herein, increased therapeutic benefit may result by alsoproviding the patient with another therapeutic agent for diabetes. Inany case, regardless of the disease, disorder or condition beingtreated, the overall benefit experienced by the patient may simply beadditive of the two therapeutic agents or the patient may experience asynergistic benefit.

Specific, non-limiting examples of possible combination therapiesinclude use of certain compounds of the invention with anti-cancer(chemotherapeutic) drugs. Classes of anti-cancer drugs include, but arenot limited to: alkylating agents, anti-metabolites, antimitotics,checkpoint inhibitors, plant alkaloids and terpenoids, topoisomeraseinhibitors, cytotoxic antibiotics, aromatase inhibitors, angiogenesisinhibitors, anti-steroids and anti-androgens, mTOR inhibitors, tyrosinekinase inhibitors, and others.

For use in cancer and neoplastic diseases a PTPN11 (SHP2) inhibitor maybe optimally used together with one or more of the followingnon-limiting examples of anti-cancer agents:

-   -   (1) alkylating agents, including but not limited to carmustine,        chlorambucil (LEUKERAN), cisplatin (PLATIN), carboplatin        (PARAPLATIN), oxaliplatin (ELOXATIN), streptozocin (ZANOSAR),        busulfan (MYLERAN), dacarbazine, ifosfamide, lomustine (CCNU),        melphalan (ALKERAN), procarbazine (MATULAN), temozolomide        (TEMODAR), thiotepa, and cyclophosphamide (ENDOXAN);    -   (2) anti-metabolites, including but not limited to cladribine        (LEUSTATIN), mercaptopurine (PURINETHOL), thioguanine,        pentostatin (NIPENT), cytosine arabinoside (cytarabine, ARA-C),        gemcitabine (GEMZAR), fluorouracil (5-FU, CARAC), capecitabine        (XELODA), leucovorin (FUSILEV), methotrexate (RHEUMATREX),        raltitrexed;    -   (3) antimitotics, which are often plant alkaloids and        terpenoids, or derivatives thereof, including but not limited to        taxanes such as docetaxel (TAXITERE) and paclitaxel (ABRAXANE,        TAXOL); vinca alkaloids such as vincristine (ONCOVIN),        vinblastine, vindesine, and vinorelbine (NAVELBINE);    -   (4) checkpoint inhibitors, such as anti-PD-1 or PD-L1 antibodies        pembrolizumab (KEYTRUDA), nivolumab (OPDIVO), MEDI4736, and        MPDL3280A; anti-CTLA-4 antibody ipilimumab (YERVOY); and those        that target LAG3 (lymphocyte activation gene 3 protein), KIR        (killer cell immunoglobulin-like receptor), 4-1BB (tumour        necrosis factor receptor superfamily member 9), TIM3 (T-cell        immunoglobulin and mucin-domain containing-3) and OX40 (tumour        necrosis factor receptor superfamily member 4);    -   (5) topoisomerase inhibitors, including but not limited to        camptothecin (CTP), irinotecan (CAMPTOSAR), topotecan        (HYCAMTIN), teniposide (VUMON), and etoposide (EPOSIN);    -   (6) cytotoxic antibiotics, including but not limited to        actinomycin D (dactinomycin, COSMEGEN), bleomycin (BLENOXANE)        doxorubicin (ADRIAMYCIN), daunorubicin (CERUBIDINE), epirubicin        (ELLENCE), fludarabine (FLUDARA), idarubicin, mitomycin        (MITOSOL), mitoxantrone (NOVANTRONE), plicamycin;    -   (7) aromatase inhibitors, including but not limited to        aminoglutethimide, anastrozole (ARIMIDEX), letrozole (FEMARA),        vorozole (RIVIZOR), exemestane (AROMASIN);    -   (8) angiogenesis inhibitors, including but not limited to        genistein, sunitinib (SUTENT) and bevacizumab (AVASTIN);    -   (9) anti-steroids and anti-androgens such as aminoglutethimide        (CYTADREN), bicalutamide (CASODEX), cyproterone, flutamide        (EULEXIN), nilutamide (NILANDRON);    -   (10) tyrosine kinase inhibitors, including but not limited to        imatinib (GLEEVEC), erlotinib (TARCEVA), lapatininb (TYKERB),        sorafenib (NEXAVAR), and axitinib (INLYTA);    -   (11) mTOR inhibitors such as everolimus, temsirolimus (TORISEL),        and sirolimus;    -   (12) monoclonal antibodies such as trastuzumab (HERCEPTIN) and        rituximab (RITUXAN);    -   (13) other agents, such as amsacrine; Bacillus Calmette-Guérin        (B-C-G) vaccine; buserelin (ETILAMIDE); chloroquine (ARALEN);        clodronate, pamidronate, and other bisphosphonates; colchicine;        demethoxyviridin; dichloroacetate; estramustine; filgrastim        (NEUPOGEN); fludrocortisone (FLORINEF); goserelin (ZOLADEX);        interferon; leucovorin; leuprolide (LUPRON); levamisole;        lonidamine; mesna; metformin; mitotane (o,p′-DDD, LYSODREN);        nocodazole; octreotide (SANDOSTATIN); perifosine; porfimer        (particularly in combination with photo- and radiotherapy);        suramin; tamoxifen; titanocene dichloride; tretinoin; anabolic        steroids such as fluoxymesterone (HALOTESTIN); estrogens such as        estradiol, diethylstilbestrol (DES), and dienestrol; progestins        such as medroxyprogesterone acetate (MPA) and megestrol; and        testosterone.

In any case, the multiple therapeutic agents (at least one of which is acompound disclosed herein) may be administered in any order or evensimultaneously. If simultaneously, the multiple therapeutic agents maybe provided in a single, unified form, or in multiple forms (by way ofexample only, either as a single pill or as two separate pills). One ofthe therapeutic agents may be given in multiple doses, or both may begiven as multiple doses. If not simultaneous, the timing between themultiple doses may be any duration of time ranging from a few minutes tofour weeks.

Thus, in another aspect, certain embodiments provide methods fortreating PTPN11-mediated disorders in a human or animal subject in needof such treatment comprising administering to said subject an amount ofa compound disclosed herein effective to reduce or prevent said disorderin the subject, in combination with at least one additional agent forthe treatment of said disorder that is known in the art. In a relatedaspect, certain embodiments provide therapeutic compositions comprisingat least one compound disclosed herein in combination with one or moreadditional agents for the treatment of PTPN11-mediated disorders.

In some embodiments, methods described herein are used to treat adisease condition comprising administering to a subject in need thereofa therapeutically effective amount of a compound of Formula I orpharmaceutically acceptable salt thereof, wherein the condition iscancer which has developed resistance to chemotherapeutic drugs and/orionizing radiation.

In some embodiments, methods described herein are used to treat adisease condition comprising administering to a subject in need thereofa therapeutically effective amount of a compound of Formula I orpharmaceutically acceptable salt thereof, wherein the condition iscancer which has developed resistance to chemotherapeutic drugs and/orionizing radiation.

The compounds, compositions, and methods disclosed herein are useful forthe treatment of disease. In certain embodiments, the disease is one ofdysregulated cellular proliferation, including cancer. The cancer may behormone-dependent or hormone-resistant, such as in the case of breastcancers. In certain embodiments, the cancer is a solid tumor. In otherembodiments, the cancer is a lymphoma or leukemia. In certainembodiments, the cancer is and a drug resistant phenotype of a cancerdisclosed herein or known in the art. Tumor invasion, tumor growth,tumor metastasis, and angiogenesis may also be treated using thecompositions and methods disclosed herein. Precancerous neoplasias arealso treated using the compositions and methods disclosed herein.

Cancers to be treated by the methods disclosed herein include coloncancer, breast cancer, ovarian cancer, lung cancer and prostate cancer;cancers of the oral cavity and pharynx (lip, tongue, mouth, larynx,pharynx), esophagus, stomach, small intestine, large intestine, colon,rectum, liver and biliary passages; pancreas, bone, connective tissue,skin, cervix, uterus, corpus endometrium, testis, bladder, kidney andother urinary tissues, including renal cell carcinoma (RCC); cancers ofthe eye, brain, spinal cord, and other components of the central andperipheral nervous systems, as well as associated structures such as themeninges; and thyroid and other endocrine glands. The term “cancer” alsoencompasses cancers that do not necessarily form solid tumors, includingHodgkin's disease, non-Hodgkin's lymphomas, multiple myeloma andhematopoietic malignancies including leukemias (Chronic LymphocyticLeukemia (CLL), Acute Lymphocytic Leukemia (ALL), Chronic MyelogenousLeukemia (CML), Acute Myelogenous Leukemia (AML),) and lymphomasincluding lymphocytic, granulocytic and monocytic. Additional types ofcancers which may be treated using the compounds and methods of theinvention include, but are not limited to, adenocarcinoma, angiosarcoma,astrocytoma, acoustic neuroma, anaplastic astrocytoma, basal cellcarcinoma, blastoglioma, chondrosarcoma, choriocarcinoma, chordoma,craniopharyngioma, cutaneous melanoma, cystadenocarcinoma,endotheliosarcoma, embryonal carcinoma, ependymoma, Ewing's tumor,epithelial carcinoma, fibrosarcoma, gastric cancer, genitourinary tractcancers, glioblastoma multiforme, head and neck cancer,hemangioblastoma, hepatocellular carcinoma, hepatoma, Kaposi's sarcoma,large cell carcinoma, leiomyosarcoma, leukemias, liposarcoma, lymphaticsystem cancer, lymphomas, lymphangiosarcoma,lymphangioendotheliosarcoma, medullary thyroid carcinoma,medulloblastoma, meningioma mesothelioma, myelomas, myxosarcomaneuroblastoma, neurofibrosarcoma, oligodendroglioma, osteogenic sarcoma,epithelial ovarian cancer, papillary carcinoma, papillaryadenocarcinomas, paraganglioma, parathyroid tumours, pheochromocytoma,pinealoma, plasmacytomas, retinoblastoma, rhabdomyosarcoma, sebaceousgland carcinoma, seminoma, skin cancers, melanoma, small cell lungcarcinoma, non-small cell lung carcinoma, squamous cell carcinoma, sweatgland carcinoma, synovioma, thyroid cancer, uveal melanoma, and Wilm'stumor.

In certain embodiments, the compositions and methods disclosed hereinare useful for preventing or reducing tumor invasion and tumormetastasis.

Besides being useful for human treatment, certain compounds andformulations disclosed herein may also be useful for veterinarytreatment of companion animals, exotic animals and farm animals,including mammals, rodents, and the like. More preferred animals includehorses, dogs, and cats.

List of Abbreviations

NaOH=sodium hydroxide; M=molar; mL=milliliter; h=hour; min.=minute;HCl=hydrogen chloride; H₂O=water; MS=mass spectrometry; ES+=electrospraypositive ionization; ¹H-NMR=proton nuclear magnetic resonance;MHz=megahertz; DMSO-d₆=dimethyl sulfoxide deuterated-6; H=hydrogen;rt=room temperature; ° C.=Celsius; Br₂=bromine; NaHSO₃=sodium bisulfite;NMP=ethyl-2-pyrrolidone; MW=microwave; KF=potassium fluoride;Pd(dppf)Cl₂=[1, 1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloride PE=petroleum ether; EA=ethyl acetate; CDCl₃=deuteratedchloroform; MeOH=methanol; D₂O=deuterated water; HPLC=high pressureliquid chromatography; DMSO=dimethyl sulfoxide; MeCN=acetonitrile;NIS=N-iodosuccinimide; DMF=dimethylformamide; K₃PO₄=potassium phosphate,tribasic; Na=nitrogen; TBDMS=TBS=tert-butyldimethylsilyl;TFA=trifluoroacetic acid; DCM=dichloromethane; K₂CO₃=potassiumcarbonate; ul=microliter.

SYNTHETIC INTERMEDIATES

The following synthetic intermediates can be used to practice thepresent invention.

Intermediate 101 tert-Butyl methyl(4-methylpiperidin-4-yl)carbamate

tert-Butyl 1-benzyl-4-methylpiperidin-4-yl carbamate

To a solution of tert-butyl 4-methylpiperidin-4-yl carbamate (214 mg,1.0 mmol) and K₂CO₃ (276 mg, 2.0 mmol) in DMF (10 mL) was added benzylbromide (178 mg, 1.05 mmol). The reaction mixture was stirred at 50° C.for overnight. H₂O was added and extracted with EtOAc. The organic layerwas separated and washed with brine, dried over Na₂SO₄, filtered, andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (Petroleum ether:EtOAc=2:1) to give tert-butyl1-benzyl-4-methylpiperidin-4-yl carbamate as a colorless oil (267 mg,88%).

MS (ES+) C₁₈H₂₈N₂O₂ requires: 304, found: 305 [M+H]+.

1-Benzyl-N,4-dimethylpiperidin-4-amine

To a solution of the product from the previous step (267 mg, 0.88 mmol)in dry THF (10 mL) was added LiAlH₄ (100 mg, 2.64 mmol) slowly. Thereaction mixture was heated to reflux for overnight. After cooled to rt,2˜3 drops of H₂O was added and filtered. The solid was washed by EtOAc.The combined organics were concentrated to give the title compound as acolorless oil (180 mg, 94%).

MS (ES+) C₁₄H₂₂N₂ requires: 218, found: 219 [M+H]+.

tert-Butyl 1-benzyl-4-methylpiperidin-4-yl(methyl)carbamate

To a solution of the product from the previous step (180 mg, 0.82 mmol)and (Boc)₂O (268 mg, 1.23 mmol) in CH₂Cl₂ (10 mL) was added TEA (166 mg,1.64 mmol). The reaction mixture was stirred at rt for 6 h. The solventwas removed and the residue was purified by silica gel columnchromatography (Petroleum ether:EtOAc=2:1) to give the title compound asa colorless oil (190 mg, 73%).

MS (ES+) C₁₉H₃₀N₂O₂ requires: 318, found: 319 [M+H]+.

tert-Butyl methyl(4-methylpiperidin-4-yl)carbamate

A solution of the product from the previous step (190 mg, 0.6 mmol) inMeOH (10 mL) was hydrogenated using 10% Pd/C (20 mg) as catalyst at 75°C. under atmospheric pressure for overnight. The catalyst was removed byfiltration on CELITE™ and the solvent was evaporated under reducedpressure to give the title compound as a colorless oil (120 mg, 88%).

MS (ES+) C₁₂H₂₄N₂O₂ requires: 228, found: 229 [M+H]+. ¹H NMR (500 MHz,CDCl₃) δ 2.84-2.8 (m, 5H), 2.23-2.18 (m, 2H), 1.71-1.67 (m, 4H), 1.46(s, 9H), 1.28 (s, 3H).

Intermediate 102(R)—N—((R)-1-(4-Methoxyphenyl)ethyl)-8-azaspiro[4.5]decan-1-amine

(R)-tert-butyl1-((R)-1-(4-methoxyphenyl)ethylamino)-8-azaspiro[4.5]decane-8-carboxylate

To a solution of tert-butyl 1-oxo-8-azaspiro[4.5]decane-8-carboxylate(2.0 g, 7.9 mmol) in THF (15 mL) was added(R)-1-(4-methoxyphenyl)ethanamine (1.79 g, 11.9 mmol) and Ti(OEt)₄ (2mL) at RT under N₂, then stirred at 85° C. for 18 h. The mixture wasconcentrated in vacuo, then MeOH (10 mL) was added at RT, followed bythe slow addition of LiBH₄ (0.33 g, 15.8 mmol). The mixture was stirredat RT for 2 h. The reaction was then quenched with H₂O (5 mL) andextracted with EtOAc (15 mL×3). The organic layer was separated andwashed with brine, dried over Na₂SO₄, filtered, and concentrated underreduced pressure to give the title compound as a colorless oil (2.0 g,66%).

MS (ES+) C₂₃H₃₆N₂O₃ requires: 388, found: 389 [M+H]⁺.

(R)—N—((R)-1-(4-methoxyphenyl)ethyl)-8-azaspiro[4.5]decan-1-amine

A mixture of the product from the previous step (2.0 g, 5.2 mmol) inHCl/MeOH (3 M, 10 mL) was stirred at RT for 2 h. The mixture was thenconcentrated in vacuo. An aqueous solution of NaOH was then added toadjust the pH to 1012. The mixture was extracted with EtOAc (15 mL×3).The combined organic layers were separated and washed with brine, driedover Na₂SO₄, filtered, and concentrated under reduced pressure to givethe crude title product as a colorless oil (1.2 g, 86%), which was useddirectly without further purification.

MS (ES+) C₁₈H₂₈N₂O requires: 288, found: 289 [M+H]⁺.

Intermediate 103(S)—N—((R)-1-(4-Methoxyphenyl)ethyl)-2-oxa-8-azaspiro[4.5]decan-4-amine

tert-Butyl 4-hydroxy-2-oxa-8-azaspiro[4.5]decane-8-carboxylate

To a solution of 2-oxa-8-azaspiro[4.5]decan-4-ol (1.0 g, 6.4 mmol) inCH₂Cl₂ (15 mL), was added di-tert-butyl dicarbonate (1.7 g, 7.6 mmol) atRT, then Et₃N (1.2 mL, 12.8 mmol) was added at RT. The reaction mixturewas stirred at RT for 2 h, quenched with H₂O (5 mL) and extracted withEtOAc (15 mL×3). The organic layer was separated and washed with brine,dried over Na₂SO₄, filtered, and concentrated under reduced pressure togive the title compound as a colorless oil (1.5 g, 90%), which was useddirectly without further purification.

MS (ES+) C₁₃H₂₃NO₄ requires: 257, found: 280 [M+Na]⁺.

tert-Butyl 4-oxo-2-oxa-8-azaspiro[4.5]decane-8-carboxylate

To a solution of the product from the previous step (1.5 g, 5.8 mmol) inCH₂Cl₂ (15 mL) was added Dess-Martin reagent (3.7 g, 8.7 mmol) at rt.The resulting mixture was stirred at rt overnight. The reaction mixturewas filtered, then quenched with H₂O (5 mL) and extracted with EtOAc (15mL×3). The organic layer was separated and washed with brine, dried overNa₂SO₄, filtered, and concentrated under reduced pressure. The residuewas purified by silica gel column chromatography (Petroleumether:EtOAc=5:1) to give the title compound as a colorless oil (1.2 g,86%).

MS (ES+) C₁₃H₂₁NO₄ requires: 255, found: 200 [M-55]⁺.

(S)-tert-Butyl4-((R)-1-(4-methoxyphenyl)ethylamino)-2-oxa-8-azaspiro[4.5]-decane-8-carboxylate

To a solution of the product from the previous step in THF (15 mL) wasadded (R)-1-(4-methoxyphenyl)ethanamine (1.06 g, 7.06 mmol) and Ti(OEt)₄(2 mL) at RT under N₂, then stirred at 85° C. for 18 h. The residue wasconcentrated in vacuo, then MeOH (10 mL) was added. LiBH₄ (0.35 g, 14.8mmol) was added at RT slowly, then the mixture was stirred at RT for 2h. The reaction was quenched with the addition of H₂O (5 mL). Themixture was extracted with EtOAc (15 mL×3). The organic layer wasseparated and washed with brine, dried over Na₂SO₄, filtered, andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (petroleum ether:EtOAc=4:1) to give the titlecompound as a colorless oil (1.3 g, 72%).

MS (ES+) C₂₂H₃₄N₂O₄ requires: 390, found: 391 [M+H]⁺.

(S)—N—((R)-1-(4-Methoxyphenyl)ethyl)-2-oxa-8-azaspiro[4.5]decan-4-amine

A mixture of (5)-tert-butyl4-((R)-1-(4-methoxyphenyl)ethylamino)-2-oxa-8-azaspiro[4.5]decane-8-carboxylate(1.3 g, 3.3 mmol) in HCl/MeOH (3 M, 10 mL) was stirred at RT for 2 h.Concentrated in vacuo and aqueous solution of NaOH was added to adjustthe pH to 10-12, extracted with EtOAc (25 mL×3). The organic layer wasseparated and washed with brine, dried over Na₂SO₄, filtered, andconcentrated under reduced pressure to give the crude(S)—N—((R)-1-(4-methoxyphenyl)ethyl)-2-oxa-8-azaspiro[4.5]decan-4-amineas a colorless oil (800 mg, yield: 89%) which was used directly withoutfurther purification.

MS (ES+) C₁₇H₂₆N₂O₂ requires: 290, found: 291 [M+H]⁺.

Intermediate 104 Benzyl 4-(hydroxymethyl)piperidin-4-yl carbamatehydrochloride

tert-Butyl4-(benzyloxycarbonylamino)-4-(hydroxymethyl)piperidine-1-carboxylate

To a solution of tert-butyl4-amino-4-(hydroxymethyl)piperidine-1-carboxylate (355 mg, 1.54 mmol)and benzyl chloroformate (288 mg, 1.69 mmol) in CH₂Cl₂ (20 mL) was addedDIPEA (596 mg, 4.62 mmol) at 0° C. The reaction mixture was stirred atRT for overnight. The solvent was removed and the residue was purifiedby silica gel column chromatography (Petroleum ether:EtOAc=2:1) to givethe titled compound as a white solid (450 mg, 80%).

MS (ES+) C₁₉H₂₈N₂O₅ requires: 364, found: 387.2 [M+Na]⁺. ¹H NMR (500MHz, DMSO-d₆) δ 7.40-7.31 (m, 5H), 6.94 (s, 1H), 4.98 (s, 2H), 4.73 (t,J=6.0 Hz, 1H), 3.65-3.61 (m, 2H), 3.41 (d, J=6.0 Hz, 2H), 2.93-2.89 (m,2H), 1.95-1.92 (m, 2H), 1.40-1.35 (m, 10H).

Benzyl 4-(hydroxymethyl)piperidin-4-yl carbamate hydrochloride

A solution of the product from the previous step (182 mg, 0.5 mmol) inHCl/MeOH (4M, 2 mL) was stirred at RT for 4 h. The solvent was removedunder reduced pressure to give the title compound as a colorless oil(150 mg, 100%) which was used directly without further purification.

MS (ES+) C₁₄H₂₁ClN₂O₃ requires: 264, found: 265.3 [M+H]⁺.

Intermediate 105 Benzyl 4-(fluoromethyl)piperidin-4-yl carbamatehydrochloride

tert-Butyl4-(benzyloxycarbonylamino)-4-(fluoromethyl)piperidine-1-carboxylate

To a solution of tert-butyl4-(benzyloxycarbonylamino)-4-(hydroxymethyl)-piperidine-1-carboxylate(255 mg, 0.7 mmol) in CH₂Cl₂ (10 mL) was added diethylaminosulfurtrifluoride (147 mg, 0.9 mmol) at 0° C. The resulting mixture wasstirred at 5° C. for 3 h. The solvent was removed and the residue waspurified by silica gel column chromatography (Petroleum ether:EtOAc=4:1)to give the title compound as a white solid (180 mg, 70%).

MS (ES+) C₁₉H₂₇FN₂O₄ requires: 366, found: 389.2 [M+Na]⁺.

Benzyl 4-(fluoromethyl)piperidin-4-yl carbamate hydrochloride

A solution of the product from the previous step (92 mg, 0.25 mmol) inHCl/MeOH (4M, 2 mL) was stirred at RT for 4 h. The solvent was removedunder reduced pressure to give the title compound as a colorless oil (75mg, 100%) which was used directly without further purification.

MS (ES+) C₁₄H₂₀ClFN₂O₂ requires: 266, found: 267 [M+H]⁺.

Intermediate 106(2-Chloropyridin-3-yl)(3,5-dichloropyrazin-2-yl)methanone

(2-Chloropyridin-3-yl)(3,5-dichloropyrazin-2-yl)methanol

To a −78° C. solution of LDA (2.0M in hexane, 22.0 mmol) in dry THF (40mL), under argon was slowly added 2,6-dichloropyrazine (1.65 g, 11.1mmol) in THF (10 mL). After addition was completed, the resultingmixture was stirred at −78° C. for an additional 1 h, then2-chloronicotinaldehyde (2.34 g, 16.6 mmol) in THF (10 mL) was addeddropwise. The reaction mixture was stirred for another hour, thenquenched with hydrochloric acid (3.6 mL)/EtOH (15 mL)/THF (18 mL)mixture, and warmed to RT. The reaction mixture was diluted withsaturated aqueous NaHCO₃ and extracted with EtOAc. The organic layer wasseparated and washed with brine, dried over Na₂SO₄, filtered, andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (Petroleum ether:EtOAc=4:1) to give the titlecompound as a yellow solid (880 mg, 27%).

MS (ES+) C₁₀H₆C₁₃N₃O requires: 289, found: 290 [M+H]⁺.

(2-Chloropyridin-3-yl)(3,5-dichloropyrazin-2-yl)methanone

To a solution of the product from the previous step (0.88 g, 3.0 mmol)in CH₂Cl₂ (30 mL) was added solid MnO₂ (5.28 g, 60.0 mmol) in portions.The resulting mixture was stirred at RT overnight. The reaction mixturewas filtered, and the filtrate was concentrated under reduced pressure.The residue was purified by silica gel column chromatography (Petroleumether:EtOAc=4:1) to give the title compound as a yellow solid (380 mg,43%).

MS (ES+) C₁₀H₄Cl₃N₃O requires: 287, found: 288 [M+H]⁺.

Intermediate 107(3-Chloropyridin-4-yl)(3,5-dichloropyrazin-2-yl)methanone

(3-Chloropyridin-4-yl)(3,5-dichloropyrazin-2-yl)methanol

To a −78° C. solution of LDA (2.0M in hexane, 22.0 mmol) in dry THF (40mL), under argon was slowly added 2,6-dichloropyrazine (1.65 g, 11.1mmol) in THF (5 mL). After addition was completed, the resulting mixturewas stirred at −78° C. for an additional 1 h, then3-chloroisonicotinaldehyde (2.34 g, 16.6 mmol) in THF (5 mL) was addeddropwise. The reaction mixture was stirred for another hour, thenquenched with hydrochloric acid (3.6 mL)/EtOH (15 mL)/THF (18 mL)mixture, and warmed to rt. The reaction mixture was diluted withsaturated aqueous NaHCO₃ and extracted with EtOAc. The organic layer wasseparated and washed with brine, dried over Na₂SO₄, filtered, andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (Petroleum ether:EtOAc=2:1) to give the crudetitle compound as a yellow solid (900 mg) which was used in next stepwithout further purification.

MS (ES+) C₁₀H₆Cl₃N₃O requires: 289, found: 290 [M+H]⁺.

(3-Chloropyridin-4-yl)(3,5-dichloropyrazin-2-yl)methanone

To a solution of the crude product from the previous step (0.9 g, 3.1mmol) in CH₂Cl₂ (30 mL) was added solid MnO₂ (5.46 g, 62.0 mmol) inportions. The resulting mixture was stirred at rt overnight. Thereaction mixture was filtered, and the filtrate was concentrated underreduced pressure. The residue was purified by Prep-HPLC to give thetitle compound as a yellow solid (118 mg, 4% over 2 steps).

MS (ES+) C₁₀H₄Cl₃N₃O requires: 287, found: 288 [M+H]⁺.

Intermediate 108(3-Chloro-2-(4-methoxybenzylamino)pyridin-4-yl)(3,5-dichloropyrazin-2-yl)methanone

(2,3-Dichloropyridin-4-yl)methanol

A mixture of 2,3-dichloroisonicotinic acid (19.2 g, 10 mmol) in BH₃/THF(1 M, 300 mL) was stirred at 60° C. for 3 h. After cooling to RT, MeOH(100 mL) was slowly added, then the reaction mixture was concentratedand diluted with H₂O (100 mL) and extracted with EtOAc (200 mL×3). Theorganic layer was separated and washed with brine, dried over Na₂SO₄,filtered and concentrated under reduced pressure to give the crude titlecompound (15.4 g, yield 87%) as a yellow solid which was used directlywithout further purification.

MS (ES+) C₆H₅Cl₂NO requires: 177, found: 178 [M+H]+.

(3-Chloro-2-(4-methoxybenzylamino)pyridin-4-yl)methanol

A mixture of the product from the previous step (15.4 g, 86.5 mmol) in(4-methoxyphenyl)methanamine (15 mL) was stirred at 150° C. for 4 h. Themixture was purified by silica gel column chromatography (Petroleumether:EtOAc=4:1˜2:1) to give the title compound as a yellow solid (20 g,yield 83.3%).

MS (ES+) C₁₄H₁₅ClN₂O₂ requires: 278, found: 279 [M+H]+.

3-Chloro-2-(4-methoxybenzylamino)isonicotinaldehyde

To a solution of the product from the previous step (20 g, 71.9 mmol) inDCM (2 L) was added MnO₂ (125 g, 1.38 mol) in portionwise. The mixturewas stirred at RT overnight. The reaction was filtered and the filtratewas purified by silica gel column chromatography (Petroleumether:EtOAc=10:1˜5:1) to give the title compound as a yellow solid (15g, yield 75.7%).

MS (ES+) C₁₄H₁₃ClN₂O₂ requires: 276, found: 277 [M+H]+.

(3-Chloro-2-(4-methoxybenzylamino)pyridin-4-yl)(3,5-dichloropyrazin-2-yl)methanol

To a −78° C. solution of LDA (2.0M in hexane, 22.0 mmol) in dry THF (40mL), under argon was added 2,6-dichloropyrazine (1.648 g, 11.0 mmol) inTHF (10 mL) slowly. After addition was complete, the resulting mixturewas stirred at −78° C. for an additional 1 h, then the product from theprevious step (4.55 g, 16.5 mmol) in THF (30 mL) was added dropwise. Thereaction mixture was stirred for another hour, then quenched with HCl(1.8 mL)/EtOH (7.5 mL)/THF (9.0 mL) mixture, and warmed to RT. Thereaction mixture was diluted with saturated aqueous NaHCO₃ solution andextracted with EtOAc. The organic layer was separated and washed withbrine, dried over Na₂SO₄, filtered and concentrated under reducedpressure. The residue was purified by silica gel column chromatography(Petroleum ether:EtOAc=3:1) to give the title compound as a yellow solid(500 mg, yield 10.7%).

MS (ES+) C₁₈H₁₅C₁₃N₄O₂ requires: 424, found: 425 [M+H]+.

(3-Chloro-2-(4-methoxybenzylamino)pyridin-4-yl)(3,5-dichloropyrazin-2-yl)methanone

To a solution of the product from the previous step (500 mg, 1.18 mmol)in CH₂Cl₂ (200 mL) was added solid MnO₂ (2.05 g, 23.58 mmol)portionwise. The result mixture was stirred at RT overnight. Thereaction mixture was filtered off and the filtrate was concentrated togive the titled compound as a yellow solid (480 mg, yield 96%).

MS (ES+) C₁₈H₁₃Cl₃N₄O₂ requires: 422, found: 423 [M+H]+.

Intermediate 109(3-Chloro-2-methoxypyridin-4-yl)(3,5-dichloropyrazin-2-yl)methanone

(3-Chloro-2-methoxypyridin-4-yl)methanol

Freshly prepared NaOMe in MeOH (from Na (4.12 g) in dry MeOH (45 mL))was added dropwise to a solution of (2,3-dichloropyridin-4-yl)methanol(15 g, 87.2 mmol) in dry MeOH (20 mL). The reaction mixture was refluxedovernight, allowed to cool to RT and concentrated. The resulting mixturewas quenched with H₂O (300 mL) and extracted with EtOAc (3×300 mL). Thecombined organic layers were washed with brine (3×100 mL), dried overNa₂SO₄ and concentrated in vacuo to afford crude the title compound (13g, yield 86.6%).

MS (ES+) C₇H₈ClNO₂ requires: 173, found: 174 [M+H]+.

3-Chloro-2-methoxyisonicotinaldehyde

To a solution of the product from the previous step (13 g, 75.1 mmol) inDCM (2 L) was added MnO₂ (130 g, 1.5 mol) portionwise. The mixture wasstirred at RT overnight. The reaction was filtered, and the filtrate waspurified by silica gel column chromatography (Petroleumether:EtOAc=10:1˜8:1) to give the title compound as a white solid (10 g,yield 78.1%).

MS (ES+) C₇H₆ClNO₂ requires: 171, found: 172 [M+H]⁺.

(3-Chloro-2-methoxypyridin-4-yl)(3,5-dichloropyrazin-2-yl)methanol

To a −78° C. solution of LDA (2.0M in hexane, 22.0 mmol) in dry THF (40mL) under argon was added 2,6-dichloropyrazine (1.648 g, 11.0 mmol) inTHF (10 mL) slowly. After addition was complete, the resulting mixturewas stirred at −78° C. for an additional 1 h, then the product from theprevious step (2.82 g, 16.5 mmol) in THF (10 mL) was added dropwise. Thereaction mixture was stirred for another hour, then quenched with HCl(1.8 mL)/EtOH (7.5 mL)/THF (9.0 mL) mixture, and warmed to RT. Thereaction mixture was diluted with sat. aq. NaHCO₃ solution and extractedwith EtOAc. The organic layer was separated and washed with brine, driedover Na₂SO₄, filtered, and concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography (Petroleumether:EtOAc=3:1) to give the title compound as a white solid (500 mg,yield 14.2%).

MS (ES+) C₁₁H₈Cl₃N₃O₂ requires: 319, found: 320 [M+H]⁺.

(3-Chloro-2-methoxypyridin-4-yl)(3,5-dichloropyrazin-2-yl)methanone

To a solution of the product from the previous step (500 mg, 1.56 mmol)in CH₂Cl₂ (200 mL) was added solid MnO₂ (2.71 g, 31.2 mmol) portionwise.The result mixture was stirred at RT overnight. The reaction mixture wasfiltered, and the filtrate was concentrated to give the title compoundas a white solid (480 mg, yield 96%).

MS (ES+) C₁₁H₆Cl₃N₃O₂ requires: 317, found: 318 [M+H]+.

Intermediate 110 (4-(4-Methoxybenzylamino)piperidin-4-yl)methanoldihydrochloride

tert-Butyl4-(hydroxymethyl)-4-(4-methoxybenzylamino)piperidine-1-carboxylate

To a solution of tert-butyl4-amino-4-(hydroxymethyl)piperidine-1-carboxylate (100 mg, 0.43 mmol)and K₂CO₃ (119 mg, 0.86 mmol) in DMF (5 mL) was added1-(chloromethyl)-4-methoxybenzene (81 mg, 0.52 mmol). The mixture wasstirred at 50° C. overnight. H₂O (20 mL) was added, and the resultingmixture was extracted with ETOAc (20 mL×3), dried and concentrated. Theresidue was purified by Prep-TLC eluting with PE:EtOAc=2:1 to give thetitle compound as a colorless oil (85 mg, 57%).

MS (ES+) C₁₉H₃₀N₂O₄ requires: 350, found: 351 [M+H]+.

(4-(4-Methoxybenzylamino)piperidin-4-yl)methanol dihydrochloride

A solution of the product from the previous step (85 mg, 0.24 mmol) in4M HCl/MeOH (3 mL) was stirred at RT for 4 h. The solvent was removed togive the title compound as a white solid (78 mg, 100%), which was useddirectly without further purification.

MS (ES+) C₁₄H₂₄Cl₂N₂O₂ requires: 250, found: 251.2 [M+H]+.

Intermediate 111(5-Chloro-2-(4-methoxybenzylamino)pyridin-4-yl)(3,5-dichloropyrazin-2-yl)methanone

To a solution of(5-chloro-2-(4-methoxybenzylamino)pyridin-4-yl)(3,5-dichloropyrazin-2-yl)methanol(170 mg, 0.4 mmol) in DCM (20 mL) was added Dess-Martin reagent (255 mg,0.6 mmol) at 0° C. The reaction mixture was stirred at RT for 4 h, thenpoured into aq. NaHCO₃ and extracted with EtOAc (25 mL×3). The organiclayers were dried over Na₂SO₄, filtered, and concentrated under reducedpressure. The residue was purified by Prep-TLC eluting with PE:EtOAc=3:1to give the title compound as a yellow solid (137 mg, 80%).

MS (ES+) C₁₈H₁₃Cl₃N₄O₂ requires: 422, found: 423.1 [M+H]+.

Intermediate 112(3-Amino-2-chlorophenyl)(3,5-dichloropyrazin-2-yl)methanone

(2-Chloro-3-nitrophenyl)(3,5-dichloropyrazin-2-yl)methanol

To a solution of 2,6-dichloropyrazine (1.06 g, 7.2 mmol) in THF (10 mL)was added 2 M LDA in THF (7.2 mL, 14.4 mmol) at −78° C. under N₂ slowly.The mixture was then stirred at −78° C. for 1 h. A solution of2-chloro-3-nitrobenzaldehyde (2.0 g, 10.8 mmol) in THF (5 mL) was added,and the mixture was stirred at −78° C. for another 1 h. The reaction wasthen quenched with aq. NH₄Cl (10 mL), then the mixture was extractedwith EtOAc (20 mL×3). The combined organic layers were washed withbrine, dried over Na₂SO₄ and concentrated. The residue was purified bycolumn chromatography on silica gel, eluting with PE:EtOAc=3:1 to givethe title compound as a yellow solid (1.2 g, 50%).

MS (ES+) C₁₁H₆Cl₃N₃O₃ requires: 333, found: 334 [M+H]+.

(2-Chloro-3-nitrophenyl)(3,5-dichloropyrazin-2-yl)methanone

To a solution of the product from the previous step in DCM (15 mL) wasadded MnO₂ (3.1 g, 36 mmol) at RT, then the mixture was stirred for 18h, filtered and concentrated in vacuo. The residue was purified bycolumn chromatography on silica gel, eluting with PE:EtOAc=4:1 to givethe title compound as a white solid (0.6 g, 50%).

MS (ES+) C₁₁H₄Cl₃N₃O₃ requires: 331, found: 332 [M+H]+.

(3-Amino-2-chlorophenyl)(3,5-dichloropyrazin-2-yl)methanone

To a solution of the product from the previous step (0.6 g, 1.8 mmol) inEtOH (10 mL) was added SnCl₂.2H₂O (0.8 g, 3.6 mmol) at RT. The mixturewas then stirred at 90° C. for 18 h, then concentrated in vacuo. Theresidue was purified by column chromatography on silica gel, elutingwith PE:EtOAc=1:1 to give the titled compound as a white solid (0.4 g,74%).

MS (ES+) C₁₁H₆Cl₃N₃O requires: 301, found: 302 [M+H]+.

Intermediate 113(3-Chloro-2-(methylamino)pyridin-4-yl)(3,5-dichloropyrazin-2-yl)methanone

(3-Chloro-2-(methylamino)pyridin-4-yl)methanol

To a solution of (2,3-dichloropyridin-4-yl)methanol (15.4 g, 87 mmol) inCH₃NH₂ (7 M in H₂O, 200 mL) was added MeOH (20 mL). The reaction mixturewas stirred at 120° C. for 24 h, allowed to cool to RT and concentrated.The mixture was poured into H₂O (100 mL) and extracted with EtOAc (3×300mL). The combined organic layers were washed with brine (3×100 mL),dried over Na₂SO₄ and concentrated in vacuo to afford the titledcompound crude (13 g, yield 86.6%).

MS (ES+) C₇H₉ClN₂O requires: 172, found: 173 [M+H]+.

3-Chloro-2-(methylamino)isonicotinaldehyde

To a solution of the product from the previous step (13 g, 75.5 mmol) inDCM (2 L) was added MnO₂ (131 g, 1.5 mol) portionwise. The mixture wasstirred at RT overnight. The reaction was filtered, and the filtrate waspurified by silica gel column chromatography (Petroleumether:EtOAc=10:1˜4:1) to give the title compound as a yellow solid (11g, yield 84.6%).

MS (ES+) C₇H₇ClN₂O requires: 170, found: 171 [M+H]+.

(3-Chloro-2-(methylamino)pyridin-4-yl)(3,5-dichloropyrazin-2-yl)methanol

To a −78° C. solution of LDA (2.0M in hexane, 22.0 mmol) in dry THF (40mL) under argon was added 2,6-dichloropyrazine (1.648 g, 11.0 mmol) inTHF (10 mL) slowly. After addition was complete, the resulting mixturewas stirred at −78° C. for an additional 1 h, then the product from theprevious step (2.8 g, 16.5 mmol) in THF (10 mL) was added dropwise. Thereaction mixture was stirred for another hour, then quenched with HCl(1.8 mL)/EtOH (7.5 mL)/THF (9.0 mL) mixture, and warmed to RT. Thereaction mixture was diluted with sat. aq. NaHCO₃ solution and extractedwith EtOAc. The organic layer was separated and washed with brine, driedover Na₂SO₄, filtered and concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography (Petroleumether:EtOAc=3:1) to give the title compound as a yellow solid (500 mg,yield 14.2%).

MS (ES+) C₁₁H₉Cl₃N₄O requires: 318, found: 319 [M+H]+.

(3-Chloro-2-(methylamino)pyridin-4-yl)(3,5-dichloropyrazin-2-yl)methanone

To a solution of the product from the previous step (500 mg, 1.56 mmol)in CH₂Cl₂ (200 mL) was added solid MnO₂ (2.71 g, 31.2 mmol) portionwise.The resulting mixture was stirred at RT overnight. The reaction mixturewas filtered, and the filtrate was concentrated to give the titledcompound as a yellow solid (480 mg, yield 96%).

MS (ES+) C₁₁H₇Cl₃N₄O requires: 316, found: 317 [M+H]+.

Intermediate 114(R)-2-methyl-N-(1-(4-methylpiperidin-4-yl)ethyl)propane-2-sulfinamide

tert-Butyl 4-(methoxy(methyl)carbamoyl)-4-methylpiperidine-1-carboxylate

To a solution of1-(tert-butyloxycarbonyl)-4-methylpiperidine-4-carboxylic acid (15 g,61.7 mmol), N,O-dimethylhydroxylamine hydrochloride (12 g, 123.4 mmol)and HATU (30.8 g, 80.2 mmol) in DMF (100 mL) was added TEA (25 g). Themixture was stirred at RT overnight. The mixture was diluted with EtOAc(700 mL) and washed with aq. NH₄Cl (200 mL×5). The organic phase wasdried over Na₂SO₄ and concentrated to obtain the title compound as abrown oil (15 g, 90%).

MS (ES+) C₁₄H₂₆N₂O₄ requires: 286, found: 287 [M+H]+.

tert-Butyl 4-acetyl-4-methylpiperidine-1-carboxylate

To a solution of the product from the previous step (5 g, crude) in THF(50 mL) was added MeMgCl (2M in THF, 26 mL, 52 mmol) at 0° C. Themixture was stirred at RT overnight. The mixture was poured into coldaq. NH₄Cl slowly then extracted with EtOAc (100 mL×3). The organic phasewas washed with brine (100 mL), dried with Na₂SO₄, and concentrated toobtained the title compound as a brown oil (4 g, 85%).

MS (ES+) C₁₃H₂₃NO₃ requires 241, found: 242 [M+H]+.

(R,E)-tert-Butyl4-(1-(tert-butylsulfinylimino)ethyl)-4-methylpiperidine-1-carboxylate

To a solution of the product from the previous step (2.0 g, 8.3 mmol) indry THF (20 mL) was added (R)-2-methylpropane-2-sulfinamide (2.0 g, 16.6mmol) and Ti(OEt)₄ (6 mL). The mixture was stirred at 85° C. overnight.The mixture was concentrated and use directly for the next step.

MS (ES+) C₁₇H₃₂N₂O₃S requires: 344, found: 345 [M+H]+.

tert-Butyl4-(1-((R)-1,1-dimethylethylsulfinamido)ethyl)-4-methylpiperidine-1-carboxylateand diasteromer

To a mixture of the product from the previous step (2 g, crude) in MeOH(10 mL) was added NaBH₄ (631 mg, 16.6 mmol) at 0° C. The resultingmixture was stirred at RT for 4 hours. The mixture was quenched withwater (10 mL), then concentrated under vacuum. EtOAc (50 mL) was addedand filtered through a short CELITE® column. The aqueous phase wasextracted with EtOAc (50 mL×3), then the organic phases were combinedand washed with brine (50 mL), dried with MgSO₄, concentrated andpurified by Pre-HPLC to obtain the title compound as a white solid(isomer 1: 500 mg, isomer 2: 240 mg).

MS (ES+) C₁₇H₃₄N₂O₃S requires: 346, found: 347 [M+H]+.

(R)-2-methyl-N-(1-(4-methylpiperidin-4-yl)ethyl)propane-2-sulfinamide

To a solution of tert-butyl 4-(1-((R)-1,1-dimethylethylsulfinamido)ethyl)-4-methylpiperidine-1-carboxylate(isomer 1, 200 mg) in DCM (10 mL) was added TFA (2 mL) slowly at 0° C.and stirred at this temperature for 30 min, concentrated and useddirectly for the next step.

MS (ES+) C₁₂H₂₆N₂OS requires: 246, found: 247 [M+H]+.

The same method was used to prepare the other diastereomer.

Intermediate 115(3,5-Dichloropyrazin-2-yl)(2-(4-methoxybenzylamino)-3-methylpyridin-4-yl)methanone

2-Fluoro-4-iodo-3-methylpyridine

To a solution of LDA (68 mL, 135 mmol) at −78° C. was added a solutionof 2-fluoro-3-iodopyridine (30 g, 135 mmol) in THF (100 mL), and themixture is stirred for 1 hour at −78° C. under nitrogen. MeI (25 mL, 405mmol) was then added, and the mixture was stirred for 30 min at −78° C.The mixture was quenched with sat. aq. NaHCO₃ solution at −78° C. andthen extracted with ether. The combined ether extracts were dried withMgSO₄ and concentrated in vacuo. The residue was purified by silica gelcolumn chromatography (Petroleum ether:EtOAc=4:1) to give the titlecompound as a brown solid (22 g, 69%).

MS (ES+) C₆H₅FIN requires: 237, found: 238 [M+H]+.

Methyl 2-fluoro-3-methylisonicotinate

A mixture of the product from the previous step (22 g, 93 mmol),Pd(OAc)₂ (2.2 g, 9.8 mmol), 1,1′-bisdiphenylphosphino ferrocene (5.1 g,9.2 mmol), and NaHCO₃ (46.7 g, 556 mmol) in MeOH (1 L) was stirredovernight in a CO atmosphere at 80° C. The mixture was cooled to roomtemperature, then water and sat. aq. NaHCO₃ solution were added. Themixture was then extracted with EtOAc. The organic layers was washedwith saturated brine, and then dried over anhydrous sodium sulfate. Themixture was filtered and concentrated under reduced pressure, and theobtained residue was purified by silica gel column chromatography(Petroleum ether:EtOAc=4:1) to give the title compound as a colorlessoil (12 g, 77%).

MS (ES+) C₈H₈FNO₂ requires: 169, found: 170 [M+H]+.

(2-Fluoro-3-methylpyridin-4-yl)methanol

To a solution of the product from the previous step (12 g, 71 mmol) inMeOH (100 mL) was added NaBH₄ (11 g, 290 mmol) portionwise. Theresulting mixture was stirred at RT for 0.5 h, concentrated in vacuo.The residue was purified by silica gel column chromatography (Petroleumether:EtOAc=2:1) to give the title compound as a brown solid (9 g, 90%).

MS (ES+) C₇H₈FNO requires: 141, found: 142 [M+H]+.

(2-(4-Methoxybenzylamino)-3-methylpyridin-4-yl)methanol

A solution of the product from the previous step (9.7 g, 69 mmol),methoxybenzylamine (14.1 g, 103 mmol) and K₂CO₃ (14.1 g, 103 mmol) inDMSO (100 mL) was sealed and stirred at 150° C. for 1 hour. The reactionmixture was cooled to room temperature, then poured into cold water (500mL) and extracted with EtOAc (500 mL×2). The combined EtOAc solution waswashed with brine, dried over Na₂SO₄ and concentrated. The residue waspurified by silica gel column chromatography (DCM:MeOH=100:3) to givethe title compound as a brown solid (8 g, 45%).

MS (ES+) C₁₅H₁₈N₂O₂ requires: 258, found: 259 [M+H]+.

2-(4-Methoxybenzylamino)-3-methylisonicotinaldehyde

To a solution of the product from the previous step (8 g, 31 mmol) inCH₂Cl₂ (1.5 L) was added MnO₂ (54 g, 620 mmol). The mixture was stirredat RT overnight, then filtered. The filtrate was concentrated underreduced pressure, and the obtained residue was purified by silica gelcolumn chromatography (Petroleum ether:EtOAc=4:1) to give the titlecompound as a brown solid (7.2 g, 91%).

MS (ES+) C₁₅H₁₆N₂O₂ requires: 256, found: 257 [M+H]+.

(3,5-Dichloropyrazin-2-yl)(2-(4-methoxybenzylamino)-3-methylpyridin-4-yl)-methanol

To a −78° C. solution of LDA (26 mL, 52 mmol) in dry THF (100 mL) underAr was added 2,6-dichloropyrazine (3.9 g, 26 mmol) in 20 mL THFdropwise. The resulting solution was stirred at −78° C. for 1 h, thenthe product from the previous step (6.7 g, 26 mmol) in THF (20 mL) wasadded to the mixture dropwise at −78° C. The resulting solution wasstirred at −78° C. for 1 h, then quenched with HCl (1.8 mL)/EtOH (7.5mL)/THF (9.0 mL) mixture and warmed to rt. The reaction mixture wasdiluted with sat. aq. NaHCO₃ solution and extracted with EtOAc. Thecombined organic layers were separated and washed with brine, dried overNa₂SO₄, filtered, and concentrated under reduced pressure. The residuewas purified by silica gel column chromatography (Petroleumether:EtOAc=4:1) to give the title compound as a yellow solid (1.1 g,11%).

MS (ES+) C₁₉H₁₈C₁₂N₄O₂ requires: 404, found: 405 [M+H]+.

(3,5-Dichloropyrazin-2-yl)(2-(4-methoxybenzylamino)-3-methylpyridin-4-yl)-methanone

To a solution of the product from the previous step (1.1 g, 2.7 mmol) inCH₂Cl₂ (200 mL) was added MnO₂ (4.7 g, 54 mmol). The mixture was stirredat RT overnight, filtered, and concentrated under reduced pressure Theobtained residue was purified by silica gel column chromatography(Petroleum ether:EtOAc=2:1) to give the title compound as a brown solid(600 mg, 55%).

MS (ES+) C₁₉H₁₆C₁₂N₄O₂ requires: 402, found: 403 [M+H]+.

Intermediate 116(R)—N-((1R,3S)-3-(tert-butyldimethylsilyloxy)-8-azaspiro[4.5]decan-1-yl)-2-methylpropane-2-sulfinamide

tert-Butyl2-oxo-6-oxaspiro[bicyclo[3.1.0]hexane-3,4′-piperidine]-r-carboxylate

A stirred solution oftert-butyl-1-oxo-8-azaspiro[4.5]dec-2-ene-8-carboxylate (500 mg; 1.99mmoles) in MeOH (10 mL) was added H₂O₂ (13.93 mmol, 1.58 mL) followed byNaOH (656 μmol; 131 μL) at 0° C. After 45 min, the reaction was quenchedby addition of one drop AcOH. The reaction mixture was poured into brineand extracted with EtOAc (3×25 mL). The combined organic layers werewashed with NaHSO₃, dried and concentrated to obtain the title compound(440 mg, yield 82.7%) as a light brown oil which was used directly inthe next step.

MS (ES+): C₁₋₄H₂₁NO₄ requires: 267.1, found: 290.0 [M+Na]⁺, ¹H NMR (500MHz, CDCl₃) δ 4.08-3.95 (m, 1H), 3.92 (t, J=2.0 Hz, 1H), 3.88-3.73 (m,1H), 3.48 (d, J=2.2 Hz, 1H), 2.92 (d, J=11.5 Hz, 2H), 2.44 (d, J=14.6Hz, 1H), 1.87 (d, J=14.6 Hz, 1H), 1.78 (ddd, J=13.4, 11.4, 4.3 Hz, 1H),1.70-1.62 (m, 1H), 1.45 (s, 9H), 1.32-1.18 (m, 2H).

tert-Butyl 3-hydroxy-1-oxo-8-azaspiro[4.5]decane-8-carboxylate

A solution of the product from the previous step (979 mg, 3.7 mmol) inacetone (25 mL) was treated with NaI (2.0 g, 13.5 mmol), NaOAc (1.36mmol, 111 mg) and AcOH (13.55 mmol, 776 μL) at 25° C. for 30 min. Theiodine formed from the reaction was reduced by addition of a saturatedaqueous Na₂S₂O₃ solution (25 mL), and the acetone was removed byevaporation. The remaining aqueous mixture was diluted with EtOAc (75mL) and washed with water (2×25 mL), sat. aq. Na₂CO₃ solution (3×25 mL),and brine (20 mL). The organic layer was dried (MgSO₄) and concentrated.The residue was purified on silica gel eluting with EtOAc-DCM 10-50% toobtain the title compound (819 mg, 83% yield) as a white solid.

MS (ES+): C₁₄H₂₃NO₄ requires: 269.2, found: 292.1 [M+Na]+; ¹H NMR (500MHz, CDCl₃) δ 4.67-4.56 (m, 1H), 3.99-3.75 (m, 2H), 3.10-2.90 (m, 2H),2.65 (dd, J=18.4, 5.9 Hz, 1H), 2.46-2.33 (m, 1H), 2.19-2.04 (m, 2H),1.97 (s, 1H), 1.85-1.76 (m, 1H), 1.70-1.62 (m, 2H), 1.45 (s, 9H).

tert-Butyl 3-(tert-butyldimethylsilyloxy)-1-oxo-8-azaspiro[4.5]decane-8-carboxylate

A mixture of the product from the previous step (819 mg, 3.04 mmol),imidazole (4.56 mmol, 320.12 mg) and TBDMSC1 (3.80 mmol, 590.61 mg) inDMF (5 mL) was stirred 16 h at room temperature. The reaction mixturewas poured into a separation funnel containing sat. aq NH₄Cl:H₂O (1:1,50 mL) and extracted with Et₂O (5×20 mL). The combined organic phaseswere dried over MgSO₄ and filtered, and the volatiles were removed underreduced pressure. The resulting residue was purified by silicachromatography (0-30% EtOAc/heptane eluent) to give the title compound(965 mg, 82.7% yield) as a colorless oil.

MS (ES+): C₂₀H₃₇NO₄Si requires: 383.2, found: 406.2 [M+Na]+, ¹H NMR (500MHz, CDCl₃) δ 4.47-4.42 (m, 1H), 3.92-3.74 (m, 2H), 3.04-2.84 (m, 2H),2.49 (dd, J=18.2, 5.7 Hz, 1H), 2.29 (d, J=18.1 Hz, 1H), 2.07-1.93 (m,2H), 1.75-1.67 (m, 1H), 1.64-1.56 (m, 2H), 1.40 (s, 9H), 1.24-1.21 (m,1H), 0.81 (s, 9H), 0.01 (s, 3H), −0.00 (s, 3H).

(R,E)-tert-butyl3-(tert-butyldimethylsilyloxy)-1-((R)-tert-butylsulfinylimino)-8-azaspiro[4.5]decane-8-carboxylateand (S,E)-tert-butyl3-(tert-butyldimethylsilyloxy)-1-((R)-tert-butylsulfinylimino)-8-azaspiro[4.5]decane-8-carboxylate

A solution of the product from the previous step (0.21 g, 547 μmol),Ti(OEt)₄ (2.19 mmol, 462 μL) and (R)-2-methylpropane-2-sulfinamide (1.09mmol, 132.7 mg) in THF (3 mL) was heated at 65° C. for 16 hours. Themixture was cooled to RT, quenched with sat. NaHCO₃ solution, andextracted with EtOAc (15 mL×4). The combined organic layers were washedwith brine (20 mL), dried (Na₂SO₄), filtered and concentrated, and theresidue was purified on silica gel eluting with EtOAc-PE 0-45% to obtainfirst the (R,E)-isomer (R_(f)=0.75, 74 mg, 28% yield) as a white solid:

MS (ES+): C₂₄H₄₆N₂O₄SSi requires: 486.3, found: 509.3 [M+Na]+, ¹H NMR(500 MHz, CDCl₃) δ 4.42-4.34 (m, 1H), 4.05-3.83 (m, 2H), 3.16 (dd,J=19.0, 3.3 Hz, 1H), 3.04-2.73 (m, 3H), 1.88-1.77 (m, 2H), 1.75-1.63 (m,3H), 1.40 (s, J=3.3 Hz, 9H), 1.31-1.25 (m, 1H), 1.19 (s, 9H), 0.80 (s,9H), 0.00 (d, J=3.0 Hz, 6H).

followed by the (S,E)-isomer (R_(f)=0.35, 75 mg, 28% yield) as acolorless oil:

MS (ES+): C₂₄H₄₆N₂O₄SSi requires: 486.3, found: 509.3 [M+Na]+, ¹H NMR(500 MHz, CDCl₃) δ 4.47-4.38 (m, 1H), 4.01-3.81 (m, 2H), 3.07 (dd,J=18.8, 5.6 Hz, 1H), 2.96-2.78 (m, 3H), 1.91 (d, J=13.4 Hz, 1H), 1.77(dd, J=13.5, 5.0 Hz, 2H), 1.73-1.65 (m, 2H), 1.41 (s, 9H), 1.35-1.30 (m,1H), 1.19 (s, 9H), 0.80 (s, 9H), −0.00 (s, 6H).

(1R,3S)-tert-butyl 3-(tert-butyldimethylsilyloxy)-1-((R)-1,1-dimethylethylsulfinamido)-8-azaspiro[4.5]decane-8-carboxylate

To a solution of the product from the previous step (0.072 g, 148 μmol)in THF (5 mL) was added MeOH (0.5 mL) at −78° C., followed by LiBH₄ (444μmol, 222 μL). The resulting mixture was stirred for 4 h at −78° C. Sat.NH₄CI solution was then added slowly to quench the excess ofborohydride, followed by addition of EtOAc (25 mL). The resultingmixture was vigorously stirred for 15 min and then filtered through apad of CELITE®. The volatiles were removed under reduced pressure, andthe resulting residue was purified by silica chromatography (0 to 50%EtOAc/heptane) to give the title compound (56 mg, 77% yield) as acolorless oil.

MS (ES+): C₂₄H₄₈N₂O₄SSi requires: 488.3, found: 489.3 [M+H]⁺; ¹H NMR(500 MHz, CDCl₃) δ 4.26 (s, 1H), 4.04-3.78 (m, 2H), 3.27 (s, 1H),2.95-2.75 (m, 2H), 2.29 (s, 1H), 1.891.51 (m, 7H), 1.41 (s, 9H),1.26-1.20 (m, 1H), 1.16 (s, 9H), 0.83 (s, 9H), −0.00 (s, 6H).

(R)—N-((1R,3S)-3-(tert-butyldimethylsilyloxy)-8-azaspiro[4.5]decan-1-yl)-2-methylpropane-2-sulfinamide

To the product from the previous step (50 mg, 102 μmol) in DCM (5 mL)was added TFA (0.5 mL). The mixture was stirred at RT for 2 hours, thenconcentrated to obtain the title compound (40 mg, 100% yield) as a paleoil which was used without further purification.

MS (ES+): C₁₉H₄₀N₂O₂SSi requires: 388.3, found: 389.3[M+H]⁺.

Intermediate 117 4-Aminopiperidine-4-carboxamide dihydrochloride

tert-butyl 4-amino-4-carbamoylpiperidine-1-carboxylate

To a solution of tert-butyl 4-amino-4-cyanopiperidine-1-carboxylate (50mg, 0.22 mmol) and K₂CO₃ (61 mg, 0.44 mmol) in DMSO (1 mL) was addedH₂O₂ (30% in water, 25 mg, 0.44 mmol) slowly. The resulting mixture wasstirred at RT for 72 h. The reaction mixture was quenched with aqueousNa₂S₂O₃ (15 mL), extracted with CHCl₃:i-PrOH (4:1, 30 mL×3), washed withbrine, dried over Na₂SO₄ and concentrated under reduced pressure to givethe title compound as a colorless syrup solid (60 mg, crude).

MS (ES+) C₁₁H₂₁N₃O₃ requires: 243, found 266 [M+Na]+.

4-Aminopiperidine-4-carboxamide dihydrochloride

To a solution of tert-butyl 4-amino-4-carbamoylpiperidine-1-carboxylate(60 mg, 0.25 mmol) in MeOH (0.5 mL) was added HCl/dioxane (4 M, 3 mL, 12mmol). The resulting mixture was stirred at RT for 2 h. The solidprecipitated was filtered to give the title compound as a white solid(60 mg).

MS (ES+) C₆H₁₃N₃O requires: 143, found: 144 [M+H]+.

Intermediate 118(3,5-Dichloropyrazin-2-yl)(2-(4-methoxybenzylamino)-5-methylpyridin-4-yl)methanone

Methyl 2-fluoro-5-methylisonicotinate

A mixture of 2-fluoro-4-iodo-5-methylpyridine (3.4 g, 14 mmol), Pd(OAc)₂(314 mg, 1.4 mmol), 1,1′-bisdiphenylphosphino ferrocene (776 mg, 1.4mmol), TEA (7 g, 70 mmol) in MeOH (200 mL) was stirred overnight in a COatmosphere at 80° C. The mixture was cooled to RT, then concentrated andpurified by silica gel column chromatography (Petroleum ether:EtOAc=4:1)to give the title compound as a white solid (1.5 g, 75%).

MS (ES+) C₈H₈FNO₂ requires: 169, found: 170 [M+H]+.

(2-Fluoro-5-methylpyridin-4-yl)methanol

To a solution of the product from the previous step (1.2 g, 7.1 mmol) inMeOH (20 mL) was added NaBH₄ (1.1 g, 29 mmol) portionwise. The resultingmixture was stirred at RT for 0.5 h, the reaction mixture wasconcentrated in vacuo. The residue was dissolved in EtOAc (50 mL),washed with brine (50 mL×3), and concentrated to give the title compoundas a brown solid (970 mg, crude).

MS (ES+) C₇H₈FNO requires: 141, found: 142 [M+H]+.

(2-(4-Methoxybenzylamino)-5-methylpyridin-4-yl)methanol

A solution of (2-fluoro-5-methylpyridin-4-yl)methanol (0.97 g, 6.9 mmol)in 4-methoxybenzylamine (5 mL) was sealed and stirred at 135° C. for 72hours. The reaction mixture was cooled to RT, and then purified bysilica gel column chromatography (DCM:MeOH=100:3) to give the titlecompound as a brown solid (800 mg, crude).

MS (ES+) C₁₅H₁₈N₂O₂ requires: 258, found: 259 [M+H]+.

2-(4-Methoxybenzylamino)-5-methylisonicotinaldehyde

To a solution of the product from the previous step (0.8 g, 3.1 mmol) inCH₂Cl₂ (300 mL) was added MnO₂ (5.4 g, 62 mmol), The mixture was stirredat RT overnight, then filtered. The filtrate was concentrated underreduced pressure, and the obtained residue was purified by silica gelcolumn chromatography (Petroleum ether:EtOAc=4:1) to give the titlecompound as a brown solid (720 mg, 90%).

MS (ES+) C₁₅H₁₆N₂O₂ requires: 256, found: 257 [M+H]+.

(3,5-Dichloropyrazin-2-yl)(2-(4-methoxybenzylamino)-5-methylpyridin-4-yl)methanol

To a −78° C. solution of LDA (2.6 mL, 5.2 mmol) in dry THF (10 mL) underargon was added 2,6-dichloropyrazine (390 mg, 26 mmol) in THF (4 mL)dropwise at −78° C. The resulting solution was stirred at −78° C. for 1h, then the product from the previous step (670 mg, 2.6 mmol) in THF (4mL) was added to the mixture dropwise at −78° C. The resulting solutionwas stirred at −78° C. for 1 h, then quenched with HCl (1.8 mL)/EtOH(7.5 mL)/THF (9.0 mL) mixture, and warmed to RT. The reaction mixturewas diluted with sat. aq. NaHCO₃ solution and extracted with EtOAc. Theorganic layer was separated and washed with brine, dried over Na₂SO₄,filtered, and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (Petroleum ether:EtOAc=4:1)and further purified with Pre-HPLC to give the title compound as ayellow solid (80 mg, 6%).

MS (ES+) C₁₉H₁₈C₁₂N₄O₂ requires: 404, found: 405 [M+H]+.

(3,5-Dichloropyrazin-2-yl)(2-(4-methoxybenzylamino)-5-methylpyridin-4-yl)methanone

To a solution of the product from the previous step (80 mg, 0.20 mmol)in CH₂Cl₂ (10 mL) was added Dess-Martin periodinane (127 mg, 0.3 mmol)at 0° C., the mixture was stirred at 0° C. for 1 hour, then anotherbatch of Dess-Martin periodinane (127 mg, 0.3 mmol) was added and themixture was stirred for another 4 hours at 0° C. The mixture was washedwith aq. NaHCO₃ dried over MgSO₄, and concentrated under reducedpressure, and the residue was purified by silica gel columnchromatography (Petroleum ether:EtOAc=2:1) to give the title compound asa brown solid (20 mg, 25%).

MS (ES+) C₁₉H₁₆C₁₂N₄O₂ requires: 402, found: 403 [M+H]+.

Synthetic Schemes

The following schemes can be used to practice the present invention.

A general, non-limiting synthetic strategy for the disclosed compoundsis illustrated in Scheme I, above. An appropriately substitutedpiperidine is condensed with a chlorinated pyrazine. Thepyrazolo[3,4-b]pyrazine core formed on reaction of the intermediate withhydrazine. It will be appreciated that other synthetic routes may beavailable for practice of the present invention.

Examples disclosed herein can be synthesized using the general syntheticprocedure set forth in Scheme II. Ortho metalation of the pyrazine 201can be accomplished with a metalated secondary amine (R₁₀₆)₂NLi, whichcan be prepared from (R₁₀₆)₂NH and BuLi (not shown). Without limitation,examples of suitable secondary amines (R₁₀₆)₂NH for this transformationinclude diiosopropylamine and 2,2,6,6-tetramethylpiperidine. Themetalated pyrazine is condensed with a substituted aryl carboxaldehydeto give benzylic alcohol 202. Oxidation to the ketone 203 is followed bysubstitution of the aryl halide with an appropriately substitutedpiperidine to give amine 204. Reaction with hydrazine gives thepyrazolo[3,4-b]-pyrazine ring of 205.

It will be apparent that Scheme II can be modified to accommodatefunctionality in the piperidine. A protected amine can be incorporatedinto the piperidine as an —NHP₁ group. In this scheme the group “Pi” isan appropriate amino protecting group. Without limitation, P₁ can be acarbamate protecting group such as Boc or CBz, or a labile aromaticprotecting group, such as p-methoxybenzyl. The protecting group P₁ isremoved from 205 to afford the product. A carbamate protecting group canbe removed under acid conditions to afford the product.

Examples disclosed herein can be synthesized using the general syntheticprocedure set forth in Scheme III. Condensation of spiro ketone 301(z=1) with enantiopure 1-(4-methoxy-phenyl)ethylamine), followed byreduction, gives chiral secondary amine 302. The Boc protecting group isremoved under acidic conditions, giving amine 303. In this scheme, thesymbol P₂ is intended to represent the 1-(4-methoxyphenyl)ethyl group.Reaction with a ketone such as 203 (Scheme II) affords amine 304.Reaction with hydrazine gives the pyrazolo[3,4-b]-pyrazine ring of 305.Finally, the 1-(4-methoxyphenyl)ethyl group is removed under acidconditions. This procedure can be modified to access spiro compounds ofdiffering ring sizes, i.e., z≠1. The compound may then be isolated asthe free base by methods known in the art.

Examples disclosed herein can be synthesized using the general syntheticprocedure set forth in Scheme IV. Reaction of primary amine 401 withCBz-Cl gives protected amine 402. The Boc protecting group is removedunder acidic conditions, giving amine 403, and leaving the CBz groupintact. Reaction with the previously presented ketone 203 affords amine404. Reaction with hydrazine gives the pyrazolo[3,4-b]pyrazine ring of405. Finally, the CBz group is removed under more vigorous acidconditions to give the product. The compound may then be isolated as thefree base by methods known in the art.

The invention is further illustrated by the following examples, whichmay be synthesized and isolated as free bases or as TFA salts.

Example 11-(3-(2,3-dichlorophenyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-4-methylpiperidin-4-amine

(2,3-Dichlorophenyl)(3,5-dichloropyrazin-2-yl)methanol

To a −20° C. solution of n-butyllithium (2.5M in hexane, 6.6 mmol) indry THF (20 mL), under argon, was added 2,2,6,6-tetramethylpiperidine(1.15 mL, 6.6 mmol). The resulting solution was warmed to 0° C. over 0.5hour period. The solution was then cooled to −78° C., and a solution of2,6-dichloropyrazine (824 mg, 5.5 mmol) in THF (5 mL) was slowly added.After the addition was complete, the resulting mixture was stirred at−78° C. for an additional 1 hr, then 2,3-dichlorobenzaldehyde (1.44 g,8.3 mmol) in THF (5 mL) was added dropwise. The reaction mixture wasstirred for another hour, then quenched with hydrochloric acid (1.8mL)/EtOH (7.5 mL)/THF (9.0 mL) mixture, and warmed to rt. The reactionmixture was diluted with saturated aqueous sodium bicarbonate solutionand extracted with EtOAc. The organic layer was separated and washedwith brine, dried over Na₂SO₄, filtered, and concentrated under reducedpressure. The residue was purified by silica gel column chromatography(Petroleum ether:EtOAc=4:1) to give the title compound as a yellow solid(740 mg, 41%).

MS (ES+) C₁₁H₆Cl₄N₂O requires: 322, found: 323 [M+H]+. ¹H NMR (500 MHz,DMSO-d₆) δ 8.73 (s, 1H), 7.76 (dd, J=8.0, 1.0 Hz, 1H), 7.61 (dd, J=8.0,1.0 Hz, 1H), 7.48 (t, J=8.0 Hz, 1H), 6.77 (d, J=6.0 Hz, 1H), 6.33 (d,J=6.0 Hz, 1H).

(2,3-Dichlorophenyl)(3,5-dichloropyrazin-2-yl)methanone

To a solution of the product from the previous step (97 mg, 0.3 mmol) inCH₂Cl₂ (10 mL) was added solid MnO₂ (522 mg, 6.0 mmol) in portions. Theresulting mixture was stirred at rt overnight. The reaction mixture wasfiltered, and the filtrate was concentrated to give the title compoundas a yellow solid (80 mg, 83%).

MS (ES+) C₁₁H₄Cl₄N₂O requires: 320, found: 321 [M+H]+.

tert-Butyl 1-(6-chloro-5-(2,3-dichlorobenzoyl)pyrazin-2-yl)-4-methylpiperidin-4-yl carbamate

To a solution of the product from the previous step (80 mg, 0.25 mmol)in 5 mL DMF, under N₂, was added tert-butyl 4-methylpiperidin-4-ylcarbamate (54 mg, 0.25 mmol) and K₂CO₃ (69 mg, 0.5 mmol). The resultingmixture was stirred overnight at rt and then concentrated. The residuewas dissolved in EtOAc and washed with H₂O and brine. The organic layerwas dried over Na₂SO₄, filtered, and concentrated under reducedpressure. The residue was purified by silica gel column chromatography(Petroleum ether:EtOAc=4:1) to give the title compound as a yellow oil(64 mg, 52%).

MS (ES+) C₂₂H₂₅Cl₃N₄O₃ requires: 498, found: 499 [M+H]+.

tert-Butyl1-(3-(2,3-dichlorophenyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-4-methylpiperidin-4-ylcarbamate

To a solution of the product from the previous step (64 mg, 0.13 mmol)in EtOH (10 mL) was added hydrazine hydrate (13 mg, 0.26 mmol). Theresulting mixture was refluxed under N₂ for 2 h. The solvent was removedto give the crude title compound as a yellow solid (61 mg, 100%), whichwas used directly without further purification.

MS (ES+) C₂₂H₂₆C₁₂N₆O₂ requires: 476, found: 477 [M+H]+.

1-(3-(2,3-Dichlorophenyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-4-methylpiperidin-4-amineTFA salt (1)

To a solution of the product from the previous step (61 mg, 0.13 mmol)in CH₂Cl₂ (2 mL) was added TFA (2 mL). The mixture was stirred at rt for4 h, then concentrated under reduced pressure. The residue was purifiedby Prep-HPLC under acidic condition to give the title compound as awhite solid (34.5 mg, 54%). The free base may then be isolated bymethods known in the art.

MS (ES+) C₁₉H₁₉Cl₂F₃N₆O₂ requires: 376, found: 377 [M+H]+. ¹H NMR (500MHz, DMSO-d₆) δ 13.49 (s, 1H), 8.49 (s, 1H), 7.94 (s, 3H), 7.76 (dd,J=8.0, 1.0 Hz, 1H), 7.69 (dd, J=8.0, 1.0 Hz, 1H), 7.50 (t, J=8.0 Hz,1H), 4.20-4.17 (m, 2H), 3.49-3.43 (m, 2H), 1.77-1.76 (m, 4H), 1.40 (s,3H).

The following Examples were synthesized with synthetic methods that weresimilar to that used for Example 1, and can generally be made by methodsdisclosed herein. The Examples may be made as free bases or as TFAsalts.

TABLE 1 Examples 2-14. Ex. Name Structure Spectral Data  28-(3-(2,3-dichloro- phenyl)-1H- pyrazolo[3,4-b]- pyrazin-6-yl)-2,8-diazaspiro- [4.5]decane

MS (ES+) C₂₁H₂₁Cl₂F₃N₆O₂ requires: 402, found: 403 [M + H]+. ¹H NMR (500MHz, DMSO-d₆) δ 13.41 (s, 1H), 8.91 (br, 2H), 8.47 (s, 1H), 7.75 (dd, J= 7.5, 1.5 Hz, 1H), 7.69 (dd, J = 7.5, 1,5 Hz, 1H), 7.49 (t, J = 8.0 Hz,1H), 3.81- 3.70 (m, 4H), 3.31-3.29 (m, 2H), 3.07 (s, 2H), 1.89 (t, J =7.5 Hz, 2H), 1.68-1.64 (m, 4H).  3 (1R,5S,6S)-3-(3-(2,3-dichlorophenyl)-1H- pyrazolo[3,4-b]- pyrazin-6-yl)-3-aza-bicyclo[3.1.0]hexan- 6-amine

MS (ES+) C₁₈H₁₅Cl₂F₃N₆O₂ requires: 360, found: 361 [M + H]+. ¹H NMR (500MHz, DMSO-d₆) δ 13.45 (s, 1H), 8.24 (br, 3H), 8.08 (s, 1H), 7.75 (dd, J= 8.0, 1.0 Hz, 1H), 7.68 (dd, J = 8.0, 1.0 Hz, 1H), 7.49 (t, J = 8.0 Hz,1H), 3.88 (d, J = 11.0 Hz, 2H), 3.65 (d, J = 11.0 Hz, 2H), 3.32 (m, 1H),2.16 (s, 2H).  4 (1-(3-(2,3-dichloro- phenyl)-1H- pyrazolo[3,4-b]-pyrazin-6-yl)-4- methylpiperidin-4- yl)methanamine

MS (ES+) C₂₀H₂₁Cl₂F₃N₆O₂ requires: 390, found: 391 [M + H]+. ¹H NMR (500MHz, DMSO-d₆) δ 13.40 (s, 1H), 8.46 (s, 1H), 7.76-7.68 (m, 5H), 7.50 (t,J = 8.0 Hz, 1H), 4.04- 4.01 (m, 2H), 3.53-3.48 (m, 2H), 2.81-2.79 (m,2H), 1.56-1.54 (m, 2H), 1.47-1.44 (m, 2H), 1.09 (s, 3H).  5(S)-8-(3-(2,3-dichloro- phenyl)-1H- pyrazolo[3,4-b]-pyrazin-6-yl)-8-aza- spiro[4.5]decan-1- amine

MS (ES+) C₂₂H₂₃Cl₂F₃N₆O₂ requires: 416, found: 417 [M + H]+. ¹H NMR (500MHz, DMSO-d₆) δ 13.42 (s, 1H), 8.48 (s, 1H), 7.76-7.74 (m, 4H), 7.69(dd, J = 7.5, 1.5 Hz, 1H), 7.50 (t, J = 8.0 Hz, 1H), 4.39-4.29 (m, 2H),3.23- 3.14 (m, 3H), 2.03-2.01 (m, 1H), 1.86-1.42 (m, 9H).  6 1-(3-(2,3-Dichlorophenyl)-1H- pyrazolo[3,4-b]- pyrazin-6-yl)-N,4-dimethylpiperidin-4- amine

MS (ES+) C₂₀H₂₁Cl₂F₃N₆O₂ requires: 390, found: 391 [M + H]+. ¹H NMR (500MHz, DMSO-d₆) δ 13.50 (s, 1H), 8.54 (br, 2H), 8.50 (s, 1H), 7.76 (dd, J= 8.0, 1.5 Hz, 1H), 7.69 (dd, J = 7.5, 1.5 Hz, 1H), 7.50 (t, J = 8.0 Hz,1H), 4.37-4.34 (m, 2H), 3.33- 3.28 (m, 2H), 2.55-2.53 (m, 3H), 1.84-1.77(m, 4H), 1.41 (s, 3H).  7 3-(2,3-dichloro- phenyl)-6-(1,7-diaza-spiro[3.5]nonan-7- yl)-1H-pyrazolo[3,4- b]pyrazine

MS (ES+) C₁₈H₁₈Cl₂N₆ requires: 388, found: 389 [M + H]⁺. ¹H NMR (500MHz, DMSO-d₆) δ 13.47 (s, 1H), 8.77 (br, 2H), 8.51 (s, 1H), 7.76 (dd, J= 8.0, 1.5 Hz, 1H), 7.69 (dd, J = 8.0, 1.5 Hz, 1H), 7.50 (t, J = 8.0 Hz,1H), 3.95-3.88 (m, 4H), 3.65- 3.60 (m, 2H), 2.37 (t, J = 8.5 Hz, 2H),2.09 (t, J = 6.0 Hz, 4H).  8 4-(aminomethyl)-1- (3-(2,3-dichloro-phenyl)-1H- pyrazolo[3,4-b]- pyrazin-6-yl)- piperidin-4-ol

MS (ES+) C₁₇H₁₈Cl₂N₆O requires: 392, found: 393 [M + H]⁺. ¹H NMR (500MHz, DMSO-d6) δ 13.42 (s, 1H), 8.48 (s, 1H), 7.79-7.74 (m, 4H), 7.69(dd, J = 8.0, 1.5 Hz, 1H), 7.50 (t, J = 8.0 Hz, 1H), 5.21 (s, 1H),4.21-4.18 (m, 2H), 3.48-3.44 (m, 2H), 2.83-2.81 (m, 2H), 1.67-1.59 (m,4H).  9 (1-(3-(3-chloro- phenyl)-1H- pyrazolo[3,4-b]- pyrazin-6-yl)-4-methylpiperidin-4- yl)methanamine

MS (ES+) C₁₈H₂₁ClN₆ requires: 356, found: 357 [M + H]⁺. ¹H NMR (500 MHz,DMSO-d₆) δ 13.34 (s, 1H), 8.56 (s, 1H), 8.40 (t, J = 2.0 Hz, 1H), 8.27(d, J = 7.5 Hz, 1H), 7.74 (br, 3H), 7.53 (t, J = 8.0 Hz, 1H), 7.45 (dd,8.0, 1.0 Hz, 1H), 4.04-4.01 (m, 2H), 3.53-3.49 (m, 2H), 2.81 (s, 2H),1.57- 1.45 (m, 4H), 1.10 (s, 3H). 10 1-(3-(3-chloro- phenyl)-1H-pyrazolo[3,4-b]- pyrazin-6-yl)-4- methylpiperidin-4- amine

MS (ES+) C₁₇H₁₉ClN₆ requires: 342, found: 343 [M + H]⁺. ¹H NMR (500 MHz,DMSO-d₆) δ 13.42 (s, 1H), 8.58 (s, 1H), 8.40 (t, J = 1.5 Hz, 1H), 8.27(d, J = 8.0 Hz, 1H), 7.99 (br, 3H), 7.54 (t, J = 8.0 Hz, 1H), 7.46 (dd,8.0, 1.5 Hz, 1H), 4.20-4.17 (m, 2H), 3.49-3.46 (m, 2H), 1.79-1.77 (m,4H), 1.40 (s, 3H). 11 (1-(3-(3,5-dichloro- phenyl)-1H- pyrazolo[3,4-b]-pyrazin-6-yl)-4- methylpiperidin-4-yl) methanamine

MS (ES+) C₁₈H₂₀Cl₂N₆ requires: 390, found: 391 [M + H]⁺. ¹H NMR (500MHz, DMSO-d₆) δ 13.48 (s, 1H), 8.59 (s, 1H), 8.32 (d, J= 1.5 Hz, 2H),7.75 (br, 3H), 7.63 (t, J = 2.0 Hz, 1H), 4.04-4.01 (m, 2H), 3.54-3.51(m, 2H), 2.81-2.80 (m, 2H), 1.57- 1.45 (m, 4H), 1.10 (s, 3H). 121-(3-(3,5-dichloro- phenyl)-1H- pyrazolo[3,4-b]- pyrazin-6-yl)-4-methylpiperidin-4- amine

MS (ES+) C₁₇H₁₈Cl₂N₆ requires: 376, found: 377 [M + H]⁺. ¹H NMR (500MHz, DMSO-d₆) δ 13.56 (s, 1H), 8.61 (s, 1H), 8.32 (d, J = 2.0 Hz, 2H),7.99 (br, 3H), 7.64 (t, J = 2.0 Hz, 1H), 4.20-4.17 (m, 2H), 3.50-3.47(m, 2H), 1.80-1.78 (m, 4H), 1.40 (s, 3H). 13 (1-(3-(3,4-dichloro-phenyl)-1H- pyrazolo[3,4-b]- pyrazin-6-yl)-4- methylpiperidin-4-yl)methanamine

MS (ES+) C₁₉H₂₁F₃N₆ requires: 390, found: 391 [M + H]⁺. ¹H NMR (500 MHz,DMSO-d₆) δ 13.40 (s, 1H), 8.71(s, 1H), 8.59-8.57 (m, 2H), 7.77- 7.74 (m,5H), 4.04-4.01 (m, 2H), 3.55-3.50 (m, 2H), 2.81 (s, 2H), 1.58- 1.45 (m,4H), 1.10 (s, 3H). 14 (1-(3-(3-Chloro-4- fluorophenyl)-1H-pyrazolo[3,4-b]- pyrazin-6-yl)-4- methylpiperidin-4-yl) methanamine

MS (ES+) C₁₈H₂₀ClFN₆ requires: 374, found: 375 [M + H]⁺. ¹H NMR (500MHz, DMSO-d₆) δ 13.34 (s, 1H), ), 8.55 (s, 1H), 8.50 (dd, J = 7.5, 2.0Hz, 1H), 8.31-8.28 (m, 1H), 7.77 (br, 3H), 7.56 (t, J = 9.0 Hz, 1H),4.04-4.00 (m, 2H), 3.54-3.49 (m, 2H), 2.81 (s, 2H), 1.57- 1.45 (m, 4H),1.10 (s, 3H).

Example 151-(3-(4-Chlorophenyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-4-methylpiperidin-4-amine

(4-Chlorophenyl)(3,5-dichloropyrazin-2-yl)methanol

To a −78° C. solution of LDA (2.0M in hexane, 22.0 mmol) in dry THF (40mL), under argon was slowly added 2,6-dichloropyrazine (1.648 g, 11.0mmol) in THF (10 mL). After addition was complete, the resulting mixturewas stirred at −78° C. for an additional 1 h, then 4-chlorobenzaldehyde(2.30 g, 16.5 mmol) in THF (10 mL) was added dropwise. The reactionmixture was stirred for another hour, then quenched with hydrochloricacid (1.8 mL)/EtOH (7.5 mL)/THF (9.0 mL) mixture, and warmed to rt. Thereaction mixture was diluted with saturated aqueous NaHCO₃ solution andextracted with EtOAc. The organic layer was separated and washed withbrine, dried over Na₂SO₄, filtered, and concentrated under reducedpressure. The residue was purified by silica gel column chromatography(petroleum ether:EtOAc=4:1) to give the title compound as a yellow solid(650 mg, 20%).

MS (ES+) C₁₁H₇Cl₃N₂O requires: 288, found: 289 [M+H]⁺.

(4-Chlorophenyl)(3,5-dichloropyrazin-2-yl)methanone

To a solution of (4-chlorophenyl)(3,5-dichloropyrazin-2-yl)methanol (650mg, 2.3 mmol) in CH₂Cl₂ (200 mL) was added solid MnO₂ (3.99 g, 46 mmol)in portions. The resulting mixture was stirred at rt overnight. Thereaction mixture was filtered, and the filtrate was concentrated to givethe title compound as a yellow solid (620 mg, 95%).

MS (ES+) C₁₁H₅Cl₃N₂O requires: 286, found: 287 [M+H]⁺. ¹H NMR (500 MHz,DMSO-d₆) δ 8.83 (s, 1H), 7.44-7.38 (m, 4H), 6.41 (d, J=5.7 Hz, 1H), 6.12(d, J=5.6 Hz, 1H).

tert-Butyl1-(6-chloro-5-(4-chlorobenzoyl)pyrazin-2-yl)-4-methylpiperidin-4-ylcarbamate

To a solution of (4-chlorophenyl)(3,5-dichloropyrazin-2-yl)methanone in2 mL DMF, under N₂, was added tert-butyl 4-methylpiperidin-4-ylcarbamate (53.5 mg, 0.25 mmol) and K₂CO₃ (69 mg, 0.5 mmol). Theresulting mixture was stirred overnight at RT and then poured into H₂O(20 mL). The solid was collected and dried to give the crude titlecompound as a yellow solid (120 mg) which was used directly withoutfurther purification.

MS (ES+) C₂₂H₂₆Cl₂N₄O₃ requires: 464, found: 465 [M+H]⁺.

tert-Butyl1-(3-(4-chlorophenyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-4-methylpiperidin-4-ylcarbamate

To a solution of the crude product from the previous step (120 mg, 0.23mmol) in EtOH (10 mL) was added hydrazine hydrate (23 mg, 0.46 mmol).The resulting mixture was refluxed under N₂ for 2 h. The solvent wasremoved to give the crude title compound as a yellow solid (100 mg),which was used directly without further purification.

MS (ES+) C₂₂H₂₇ClN₆O₂ requires: 442, found: 443 [M+H]⁺.

1-(3-(4-Chlorophenyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-4-methylpiperidin-4-aminetrifluoroacetate (15)

To a solution of the crude product from the previous step (100 mg) inCH₂Cl₂ (2 mL) was added TFA (2 mL). The mixture was stirred at RT for 4h, then concentrated under reduced pressure. The residue was purified byPrep-HPLC under acidic condition to give the title compound as a yellowsolid (43.4 mg, 50% over 3 steps).

MS (ES+) C₁₇H₁₉ClN₆ requires: 342, found: 343 [M+H]⁺. ¹H NMR (400 MHz,DMSO-d₆) δ 13.36 (s, 1H), 8.54 (s, 1H), 8.36 (d, J=8.6 Hz, 2H), 7.93(br, 3H), 7.57 (d, J=8.6 Hz, 2H), 4.17 (d, J=14.1 Hz, 2H), 3.49 (dd,J=13.9, 6.5 Hz, 2H), 1.78 (m, 4H), 1.40 (s, 3H).

The following Examples were synthesized with synthetic methods that weresimilar to that used for Example 15, and can generally be made bymethods disclosed herein. The Examples may be made as free bases or asTFA salts.

TABLE 2 Examples 16-20. Ex. Name Structure Spectral Data 16(1-(3-(4-chloro- phenyl)-1H- pyrazolo[3,4-b]- pyrazin-6-yl)-4-methylpiperidin- methanamine

MS (ES+) C₁₈H₂₁ClN₆ requires: 356, found: 357 [M + H]⁺. ¹H NMR (500 MHz,DMSO-d=) δ 13.28 (s, 1H), 8.52 (s, 1H), 8.35 (d, J = 8.5 Hz, 2H), 7.75(br, 3H), 7.57 (d, J = 8.5 Hz, 2H), 4.03-4.00 (m, 2H), 3.53-3.50 (m,2H), 2.80 (s, 1H), 1.57-1.47 (m, 4H), 1.10 (s, 3H). 17(R)-8-(3-(4-chloro- phenyl)-1H- pyrazolo[3,4-b]- pyrazin-6-yl)-8-aza-spiro[4.5]decan-1- amine

MS (ES+) C₂₀H₂₃ClN₆ requires: 382, found: 383 [M + H]⁺. ¹H NMR (500 MHz,DMSO-d₆) δ 13.29 (s, 1H), 8.54 (s, 1H), 8.35 (d, J = 8.5 Hz, 2H), 7.76(br, 3H), 7.57 (d, J = 8.5 Hz, 2H), 4.40-4.31 (m, 2H), 3.23-3.15 (m,3H), 2.06-1.40 (m, 10H). 18 1-(3-(3,4-dichloro- phenyl)-1H-pyrazolo[3,4-b]- pyrazin-6-yl)-4- methylpiperidin-4- amine

MS (ES+) C₁₇H₁₈Cl₂N₆ requires: 376, found: 377 [M + H]⁺. ¹H NMR (500MHz, DMSO-d₆) δ 13.49 (s, 1H), 8.59 (s, 1H), 8.56 (d, J = 2.0 Hz, 1H),8.28 (dd, J = 8.0, 2.0 Hz, 1H), 7.97 (br, 3H), 7.78 (d, J = 8.5 Hz, 1H),4.20-4.17 (m, 2H), 3.49-3.46 (m, 2H), 1.79-1.77 (m, 4H), 1.40 (s, 3H).19 1-(3-(3-Chloro-4- fluorophenyl)-1H- pyrazolo[3,4-b]- pyrazin-6-yl)-4-methylpiperidin-4- amine

MS (ES+) C₁₇H₁₈ClFN₆ requires: 360, found: 361 [M + H]⁺. ¹H NMR (500MHz, DMSO-d₆) δ 13.42 (s, 1H), 8.58 (s, 1H), 8.51 (dd, J = 8.0, 2.0 Hz,1H), 8.32-8.29 (m, 1H), 7.97 (br, 3H), 7.57 (t, J = 9.0 Hz, 1H),4.20-4.17 (m, 2H), 3.50-3.45 (m, 2H), 1.79-1.77 (m, 4H), 1.40 (s, 3H).20 1-(3-(2- Chlorophenyl)-1H- pyrazolo[3,4- b]pyrazin-6-yl)-4-methylpiperidin-4- amine

MS (ES+) C₁₇H₁₉ClN₆ requires: 342, found: 343 [M + H]⁺. ¹H NMR (500 MHz,DMSO-d₆) δ 13.40 (s, 1H), 8.48 (s, 1H), 7.96 (br, 3H), 7.76-7.74 (m,1H), 7.62-7.60 (m, 1H), 7.48-7.47 (m, 2H), 4.20- 4.17 (m, 2H), 3.48-3.43(m, 2H), 1.78-1.76 (m, 4H), 1.40 (s, 3H).

Example 214-Methyl-1-(3-(3-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)piperidin-4-amine

(3,5-Dichloropyrazin-2-yl)(3-(trifluoromethyl)phenyl)methanol

To a −78° C. solution of LDA (2.0M in hexane, 22.0 mmol) in dry THF (40mL), under argon was added slowly a solution of 2,6-dichloropyrazine(1.648 g, 11.0 mmol) in THF (10 mL). After addition was complete, theresulting mixture was stirred at −78° C. for an additional 1 h, then3-(trifluoromethyl)benzaldehyde (2.89 g, 16.5 mmol) in THF (10 mL) wasadded dropwise. The reaction mixture was stirred for another hour, thenquenched with hydrochloric acid (1.8 mL)/EtOH (7.5 mL)/THF (9.0 mL)mixture, and warmed to rt. The reaction mixture was diluted withsaturated aqueous sodium bicarbonate solution and extracted with EtOAc.The organic layer was separated and washed with brine, dried overNa₂SO₄, filtered, and concentrated under reduced pressure. The residuewas purified by silica gel column chromatography (Petroleumether:EtOAc=4:1) to give the title compound as a yellow solid (720 mg,20%).

MS (ES+) C₁₂H₇Cl₂F₃N₂O requires: 322, found: 323 [M+H]⁺. ¹H NMR (500MHz, DMSO-d₆) δ 8.82 (d, J=4.6 Hz, 1H), 7.82 (s, 1H), 7.69-7.63 (m, 2H),7.58 (t, J=7.7 Hz, 1H), 6.58 (d, J=5.7 Hz, 1H), 6.24 (d, J=5.7 Hz, 1H).

(3,5-Dichloropyrazin-2-yl)(3-(trifluoromethyl)phenyl)methanone

To a solution the product from the previous step (720 mg, 2.23 mmol) inCH₂Cl₂ (200 mL) was added solid MnO₂ (3.88, 44.6 mmol) in portions. Theresulting mixture was stirred at RT overnight. The reaction mixture wasfiltered, and the filtrate was concentrated to give the title compoundas a yellow solid (650 mg, 90%).

MS (ES+) C₁₂H₅Cl₂F₃N₂O requires: 320, found: 321 [M+H]⁺.

tert-Butyl1-(6-chloro-5-(3-(trifluoromethyl)benzoyl)pyrazin-2-yl)-4-methylpiperidin-4-ylcarbamate

To a solution of the product from the previous step (80 mg, 0.25 mmol)in 2 mL DMF, under N₂, was added tert-butyl 4-methylpiperidin-4-ylcarbamate (53.6 mg, 0.25 mmol) and K₂CO₃ (69 mg, 0.5 mmol). Theresulting mixture was stirred overnight at rt and then poured into H₂O(20 mL). The solid was collected and dried to give the title compound asa yellow solid (120 mg), which was used directly without furtherpurification.

MS (ES+) C₂₃H₂₆ClF₃N₄O₃ requires: 498, found: 499 [M+H]⁺.

tert-Butyl4-methyl-1-(3-(3-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)piperidin-4-ylcarbamate

To a solution of the crude product from the previous step (120 mg, 0.23mmol) in EtOH (10 mL) was added hydrazine hydrate (23 mg, 0.46 mmol).The resulting mixture was refluxed under N₂ for 2 h. The solvent wasremoved to give the crude title compound as a yellow solid (100 mg),which was used directly without further purification.

MS (ES+) C₂₃H₂₇F₃N₆O₂ requires: 476, found: 477 [M+H]⁺.

4-Methyl-1-(3-(3-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)-piperidin-4-aminetrifluoroacetate (21)

To a solution of the crude product from the previous step (100 mg) inCH₂Cl₂ (2 mL) was added TFA (2 mL). The mixture was stirred at RT for 4h, then concentrated under reduced pressure. The residue was purified byPrep-HPLC under acidic condition to give the title compound as a lightyellow solid (34.6 mg, 36.8% over 3 steps).

MS (ES+) C₁₈H₁₉F₃N₆ requires: 376, found: 377 [M+H]⁺. ¹H NMR (500 MHz,DMSO-d₆) δ 13.49 (s, 1H), 8.72 (s, 1H), 8.64-8.57 (m, 2H), 8.02 (br,3H), 7.76 (t, J=6.6 Hz, 2H), 4.19 (dd, J=9.4, 4.6 Hz, 2H), 3.53-3.44 (m,2H), 1.79 (d, J=4.6 Hz, 4H), 1.41 (s, 3H).

The following Examples were synthesized with synthetic methods that weresimilar to that used for Example 21, and can generally be made bymethods disclosed herein. The Examples may be made as free bases or asTFA salts.

TABLE 3 Examples 22-24 Ex. Name Structure Spectral Data 22(4-methyl-1-(3-(3- (trifluoromethyl)- phenyl)-1H- pyrazolo[3,4-b]pyrazin-6-yl)- piperidin-4-yl)- methanamine

MS (ES+) C₁₉H₂₁F₃N₆ requires: 390, found: 391 [M + H]⁺. ¹H NMR (500 MHz,DMSO-d₆) δ 13.40 (s, 1H), 8.71 (s, 1H), 8.59-8.57 (m, 2H), 7.77- 7.74(m, 5H), 4.04-4.01 (m, 2H), 3.55-3.50 (m, 2H), 2.81 (s, 2H), 1.58- 1.45(m, 4H), 1.10 (s, 3H). 23 1-(3-(2-chloro- pyridin-3-yl)-1H-pyrazolo[3,4-b]- pyrazin-6-yl)-4- methyl-piperidin-4- amine

MS (ES+) C₁₆H₁₈ClN₇ requires: 343, found: 344 [M + H]⁺. ¹H NMR (500 MHz,DMSO-d₆) δ 13.54 (s, 1H), 8.52-8.51 (m, 2H), 8.21 (dd, J =7.5, 2.0 Hz,1H), 7.96 (br, 3H), 7.58 (dd, J =8.0, 5.0 Hz, 1H), 4.20-4.17 (m, 2H),3.48-3.43 (m, 2H), 1.79- 1.77 (m, 4H), 1.40 (s, 3H). 241-(3-(2-chloro-3- fluorophenyl)-1H- pyrazolo[3,4-b]- pyrazin-6-yl)-4-methyl-piperidin-4- amine

MS (ES+) C₁₇H₁₈ClFN₆ requires: 360, found: 361 [M + H]⁺. ¹H NMR (400MHz, DMSO-d₆) δ 13.52 (s, 1H), 8.51 (s, 1H), 7.94 (br, 3H), 7.66 (t, J =4.7 Hz, 1H), 7.52 (dd, J = 6.8, 5.3 Hz, 2H), 4.19 (d, J = 14.1 Hz, 2H),3.50- 3.45 (m, 2H), 1.77 (d, J = 4.7 Hz, 4H), 1.40 (s,3H).

Example 25(1-(3-(3-Chloro-2-fluorophenyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-4-methylpiperidin-4-yl)-methanamine

(3-Chloro-2-fluorophenyl)(3,5-dichloropyrazin-2-yl)methanol

To a −78° C. solution of LDA (2.0M in hexane, 22.0 mmol) in dry THF (40mL), under argon was added a solution of 2,6-dichloropyrazine (1.648 g,11.0 mmol) in THF (10 mL). After addition was completed, the resultingmixture was stirred at −78° C. for an additional 1 h, then3-chloro-2-fluorobenzaldehyde (2.61 g, 16.5 mmol) in THF (10 mL) wasadded dropwise. The reaction mixture was stirred for another hour, thenquenched with hydrochloric acid (1.8 mL)/EtOH (7.5 mL)/THF (9.0 mL)mixture, and warmed to RT The reaction mixture was diluted withsaturated aqueous sodium bicarbonate solution and extracted with EtOAc.The organic layer was separated and washed with brine, dried overNa₂SO₄, filtered, and concentrated under reduced pressure. The residuewas purified by silica gel column chromatography (petroleumether:EtOAc=4:1) to give the title compound as a yellow solid (700 mg,20%).

MS (ES+) C₁₁H₆Cl₃FN₂O requires: 306, found: 307 [M+H]⁺. ¹H NMR (500 MHz,DMSO-d₆) δ 8.80 (s, 1H), 7.61 (t, J=6.6 Hz, 1H), 7.59-7.45 (m, 1H), 7.29(t, J=7.9 Hz, 1H), 6.66 (d, J=6.0 Hz, 1H), 6.35 (d, J=6.0 Hz, 1H).

(3-Chloro-2-fluorophenyl)(3,5-dichloropyrazin-2-yl)methanone

To a solution of the product from the previous step (700 mg, 2.3 mmol)in CH₂Cl₂ (200 mL) was added solid MnO₂ (3.99 g, 46.0 mmol) in portions.The resulting mixture was stirred at RT overnight. The reaction mixturewas filtered, and the filtrate was concentrated to give the titlecompound as a yellow solid (670 mg, 95%).

MS (ES+) C₁₁H₄Cl₃FN₂O requires: 304, found: 305 [M+H]⁺.

tert-Butyl(1-(6-chloro-5-(3-chloro-2-fluorobenzoyl)pyrazin-2-yl)-4-methylpiperidin-4-yl)methylcarbamate

To a solution of product from the previous step (76 mg, 0.25 mmol) in 2mL DMF, under N₂, was added tert-butyl (4-methylpiperidin-4-yl)methylcarbamate (57 mg, 0.25 mmol) and K₂CO₃ (69 mg, 0.5 mmol). The resultingmixture was stirred overnight at RT and then poured into H₂O (20 mL).The solid was collected and dried to give the crude title compound as ayellow solid (120 mg), which was used directly without furtherpurification.

MS (ES+) C₂₃H₂₇Cl₂FN₄O₃ requires: 496, found: 497 [M+H]⁺.

tert-Butyl(1-(3-(3-chloro-2-fluorophenyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-4-methylpiperidin-4-yl)methylcarbamate

To a solution of the crude product from the previous step (120 mg, 0.23mmol) in EtOH (10 mL) was added hydrazine hydrate (23 mg, 0.46 mmol).The resulting mixture was refluxed under N₂ for 2 h. The solvent wasremoved to give the crude title compound as a yellow solid (100 mg)which was used directly without further purification.

MS (ES+) C₂₃H₂₈ClFN₆O₂ requires: 474, found: 475 [M+H]⁺.

(1-(3-(3-Chloro-2-fluorophenyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-4-methylpiperidin-4-yl)methanaminetrifluoroacetate 25)

To a solution of the crude product from the previous step (100 mg) inCH₂Cl₂ (2 mL) was added TFA (2 mL). The mixture was stirred at RT for 4h, then concentrated under reduced pressure. The residue was purified byPrep-HPLC under acidic condition to give the title compound as a lightyellow solid (50.6 mg, 54% over 3 steps).

MS (ES+) C₁₈H₂₀ClFN₆ requires: 374, found: 375 [M+H]⁺. ¹H NMR (500 MHz,DMSO-d₆) δ 13.47 (s, 1H), 8.51 (s, 1H), 8.14-8.09 (m, 1H), 7.77 (br,3H), 7.68-7.63 (m, 1H), 7.38 (t, J=7.9 Hz, 1H), 4.03 (dd, J=9.0, 5.1 Hz,2H), 3.55-3.49 (m, 2H), 2.80 (d, J=4.6 Hz, 2H), 1.61-1.54 (m, 2H),1.49-1.43 (m, 2H), 1.10 (s, 3H).

The following Examples were synthesized with synthetic methods that weresimilar to that used for Example 25, and can generally be made bymethods disclosed herein. The Examples may be made as free bases or asTFA salts.

TABLE 4 Examples 26-32. Ex. Name Structure Spectral Data 261-(3-(3-chloro-2- fluorophenyl)-1H- pyrazolo[3,4-b]- pyrazin-6-yl)-4-methylpiperidin-4- amine

MS (ES+) C₁₇H₁₈ClFN₆ requires: 360, found: 361 [M + H]⁺. ¹H NMR (400MHz, DMSO-d₆) δ 13.55 (s, 1H), 8.53 (s, 1H), 8.13-8.09 (m, 1H), 7.98(br, 3H), 7.68-7.64 (m, 1H), 7.38 (t, J = 8.0 Hz, 1H), 4.20-4.17 (m,2H), 3.51-3.48 (m, 2H), 1.78- 1.73 (m, 4H), 1.41 (s, 3H). 27(1-(3-(2-chloro-3- methoxy phenyl)-1H- pyrazolo[3,4- b]pyrazin-6-yl)-4-methylpiperidin-4-yl) methanamine

MS (ES+) C₁₉H₂₃ClN₆O requires: 386, found: 387 [M + H]⁺. ¹H NMR (500MHz, DMSO-d₆) δ 13.27 (s, 1H), 8.43 (s, 1H), 7.72 (br, 3H), 7.41 (t, J =8.0 Hz, 1H), 7.28-7.21 (m, 2H), 4.02 (d, J= 14.2 Hz, 2H), 3.92 (s, 3H),3.50(s, 2H), 2.80 (d, J = 5.9 Hz, 2H), 1.56 (t, J = 9.6 Hz, 2H), 1.45(d, J= 13.9 Hz, 2H), 1.09 (s, 3H). 28 (1-(3-(3-chloro-2-methylphenyl)-1H- pyrazolo[3,4-b]- pyrazin-6-yl)-4-methylpiperidin-4-yl) methanamine

MS (ES+) C₁₉H₂₃ClN₆ requires: 370, found: 371 [M + H]⁺. ¹H NMR (500 MHz,DMSO-d₆) δ 13.31 (s, 1H), 8.46 (s, 1H), 7.77- 7.66 (m, 4H), 7.52 (d, J =8.0 Hz, 1H), 7.34 (t, J = 7.8 Hz, 1H), 4.02 (d, J = 14.0 Hz, 2H), 3.50(t, J = 10.1 Hz, 2H), 2.80 (d, J = 5.4 Hz, 2H), 2.47 (s, 3H), 1.57 (t, J= 9.6 Hz, 2H), 1.46 (d, J= 13.6 Hz, 2H), 1.10 (s,3H). 29(1-(3-(2-chloro- phenyl)-1H- pyrazolo[3,4-b]- pyrazin-6-yl)-4-methylpiperidin- methanamine

MS (ES+) C₁₈H₂₁ClN₆ requires: 356, found: 357 [M + H]⁺. ¹H NMR (500 MHz,DMSO-d₆) δ 13.32 (s, 1H), 8.45 (s, 1H), 7.76-7.73 (m, 4H), 7.61- 7.59(m, 1H), 7.48-7.46 (m, 2H), 4,04-4.00 (m, 2H), 3.52-3.48 (m, 2H),2.81-2.80 (m, 2H), 1.59- 1.44 (m,4H), 1.10 (s, 3H). 30(4-methyl-1-(3-(2- methylpyridin-3-yl)- 1H-pyrazolo[3,4-b]pyrazin-6-yl)- piperidin-4-yl) methanamine

MS (ES+) C₁₈H₂₃N₇ requires: 337, found: 338 [M + H]⁺. ¹H NMR (500 MHz,DMSO-d₆) δ 13.55 (s, 1H), 8.72-8.65 (m, 2H), 8.53 (s, 1H), 7.78 (br,3H), 7.68 (t, J =5.0 Hz, 1H), 4.06-4.01 (m, 2H), 3.56-3.51 (m, 2H),2.85-2.81 (m, 5H), 1.60- 1.46 (m, 4H), 1.10 (s, 3H). 31 (1-(3-(3-chloro-pyridin-4-yl)-1H- pyrazolo[3,4-b]- pyrazin-6-yl)-4-methylpiperidin-4-yl) methanamine

MS (ES+) C₁₇H₂₀ClN₇ requires: 357, found: 358 [M + H]⁺. ¹H NMR (500 MHz,DMSO-d6) δ 13.66 (s, 1H), 8.78 (s, 1H), 8.64 (d, J = 5.0 Hz, 1H), 8.53(s, 1H), 8.03 (d, J = 5.0 Hz, 1H), 7.75 (br, 3H), 4.06-4.01 (m, 2H),3.55- 3.50 (m, 2H), 2.81-2.79 (m, 2H), 1.57-1.45 (m, 4H), 1.10 (s, 3H).32 1-(3-(2-chloro-6- fluorophenyl)-1H- pyrazolo[3,4-b]- pyrazin-6-yl)-4-methylpiperidin-4- amine

MS (ES+) C₁₇H₁₈ClFN requires: 360, found: 361 [M + H]⁺. ¹H NMR (500 MHz,DMSO-d₆) δ 13.53 (s, 1H), 8.45 (s, 1H), 7.95 (br, 3H), 7.59-7.39 (m,3H), 4.20-4.17 (m, 2H), 3.48-3.43 (m, 2H), 1.78- 1.76 (m,4H), 1.40 (s,3H).

Example 33(1-(3-(4-Chloro-3-methoxyphenyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-4-methylpiperidin-4-yl)methanamine

(4-Chloro-3-methoxyphenyl)(3,5-dichloropyrazin-2-yl)methanol

To a −78° C. solution of LDA (2.0M in hexane, 22.0 mmol) in dry THF (40mL), under argon was added a solution of 2,6-dichloropyrazine (1.648 g,11.0 mmol) in THF (10 mL). After addition was completed, the resultingmixture was stirred at −78° C. for an additional 1 h, then4-chloro-3-methoxybenzaldehyde (2.81 g, 16.5 mmol) in THF (10 mL) wasadded dropwise. The reaction mixture was stirred for another hour, thenquenched with hydrochloric acid (1.8 mL)/EtOH (7.5 mL)/THF (9.0 mL)mixture, and warmed to RT. The reaction mixture was diluted withsaturated aqueous sodium bicarbonate solution and extracted with EtOAc.The organic layer was separated and washed with brine, dried overNa₂SO₄, filtered, and concentrated under reduced pressure. The residuewas purified by silica gel column chromatography (petroleumether:EtOAc=4:1) to give the title compound (600 mg, 17%).

MS (ES+) C₁₂H₉Cl₃N₂O₂ requires: 318, found: 319 [M+H]⁺.

(4-Chloro-3-methoxyphenyl)(3,5-dichloropyrazin-2-yl)methanone

To a solution of the product from the previous step (600 mg, 1.875 mmol)in CH₂Cl₂ (200 mL) was added solid MnO₂ (3.26 g, 37.5 mmol) in portions.The resulting mixture was stirred at RT overnight. The reaction mixturewas filtered, and the filtrate was concentrated to give the titlecompound as a yellow solid (495 mg, 83%).

MS (ES+) C₁₂H₇Cl₃N₂O₂ requires: 316, found: 317 [M+H]⁺.

tert-Butyl(1-(6-chloro-5-(4-chloro-3-methoxybenzoyl)pyrazin-2-yl)-4-methylpiperidin-4-yl)methylcarbamate

To a solution of the product from the previous step (80 mg, 0.25 mmol)in 2 mL DMF, under N₂, was added tert-butyl(4-methylpiperidin-4-yl)methyl carbamate (57 mg, 0.25 mmol) and K₂CO₃(69 mg, 0.5 mmol). The resulting mixture was stirred overnight at RT andthen poured into H₂O (20 mL). The solid was collected and dried to givethe crude title compound as a yellow solid (120 mg) which was useddirectly without further purification.

MS (ES+) C₂₄H₃₀Cl₂N₄O₄ requires: 508, found: 509 [M+H]⁺.

tert-Butyl(1-(3-(4-chloro-3-methoxyphenyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-4-methylpiperidin-4-yl)methylcarbamate

To a solution of the crude product from the previous step (120 mg, 0.23mmol) in EtOH (10 mL) was added hydrazine hydrate (23 mg, 0.46 mmol).The resulting mixture was refluxed under N₂ for 2 h. The solvent wasremoved to give the crude title compound as a yellow solid (100 mg),which was used directly without further purification.

MS (ES+) C₂₄H₃₁ClN₆O₃ requires: 486, found: 487 [M+H]⁺.

(1-(3-(4-Chloro-3-methoxyphenyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-4-methylpiperidin-4-yl)methanaminetrifluoroacetate (33)

To a solution of the crude product from the previous step (100 mg) inCH₂Cl₂ (2 mL) was added TFA (2 mL). The mixture was stirred at RT for 4h, then concentrated under reduced pressure. The residue was purified byPrep-HPLC under acidic condition to give the title compound as a yellowsolid (15.3 mg, 15% over 3 steps).

MS (ES+) C₁₉H₂₃ClN₆O requires: 386, found: 387 [M+H]⁺. ¹H NMR (500 MHz,DMSO-d₆) δ 13.28 (s, 1H), 8.54 (s, 1H), 8.05 (d, J=1.7 Hz, 1H), 7.99(dd, J=8.2, 1.7 Hz, 1H), 7.71 (br, 3H), 7.55 (d, J=8.2 Hz, 1H), 4.03 (d,J=14.0 Hz, 2H), 3.95 (s, 3H), 3.51 (d, J=10.0 Hz, 2H), 2.80 (d, J=5.7Hz, 2H), 1.57 (t, J=9.6 Hz, 2H), 1.46 (d, J=14.4 Hz, 2H), 1.10 (s, 3H).

The following Examples were synthesized with synthetic methods that weresimilar to that used for Example 33, and can generally be made bymethods disclosed herein. The Examples may be made as free bases or asTFA salts.

TABLE 5 Examples 34-36. Ex. Name Structure Spectral Data 34(R)-8-(3-(4-chloro-3- methoxyphenyl)-1H- pyrazolo[3,4-b]-pyrazin-6-yl)-8-aza- spiro[4.5]decan-1- amine

MS (ES+) C₂₁H₂₅ClN₆O requires: 412, found: 413 [M + H]⁺. ¹H NMR (500MHz, DMSO-d₆) δ 13.31 (s, 1H), 8.56 (s, 1H), 8.05 (d, J = 1.5 Hz, 1H),7.99 (dd, J = 8.0, 1.5 Hz, 1H), 7.80 (br, 3H), 7.55 (d, J = 8.0 Hz, 1H),4.40-4.28 (m, 2H), 4.00 (s, 3H), 3.23-3.14 (m, 3H), 2.10- 1.43 (m, 10H).35 (1-(3-(3-chloro-5- methoxyphenyl)-1H- pyrazolo[3,4-b]-pyrazin-6-yl)-4- methylpiperidin-4-yl) methanamine

MS (ES+) C₁₉H₂₃ClN₆O requires: 386, found: 387 [M + H]⁺. ¹H NMR (500MHz, DMSO-d₆) δ 13.33 (s, 1H), 8.56 (s, 1H), 7.99 (t, J = 1.5 Hz, 1H),7.84 (q, J = 1.5 Hz, 1H), 7.72 (br, 3H), 7.05 (t, J = 2.0 Hz, 1H),4.07-4.00 (m, 2H), 3.85 (s, 3H), 3.54- 3.49 (m, 2H), 2.81-2.79 (m, 2H),1.60-1.45 (m, 4H), 1.10 (s, 3H). 36 (1-(3-(2-chloro- pyridin-3-yl)-1H-pyrazolo[3,4-b]- pyrazin-6-yl)-4- methylpiperidin-4-yl) methanamine

MS (ES+) C₁₇H₂₀ClN₇ requires: 357, found: 358 [M + H]⁺. ¹H NMR (500 MHz,DMSO-d₆) δ 13.47 (s, 1H), 8.51-8.48 (m, 2H), 8.22 (dd, J = 8.0, 2.0 Hz,1H), 7.77 (br, 3H), 7.58 (dd, J = 8.0, 5.0 Hz, 1H), 4.05-4.00 (m, 2H),3.54-3.49 (m, 2H), 2.81 (s, 2H), 1.59-1.46 (m, 4H), 1.10 (s, 3H).

Example 374-(Aminomethyl)-1-(3-(2-chloro-3-fluorophenyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-piperidin-4-ol

(2-Chloro-3-fluorophenyl)(3,5-dichloropyrazin-2-yl)methanol

To a −78° C. solution of LDA (2.0M in hexane, 22.0 mmol) in dry THF (40mL), under argon was added a solution of 2,6-dichloropyrazine (1.648 g,11.0 mmol) in THF (10 mL). After addition was completed, the resultingmixture was stirred at −78° C. for an additional 1 h, then2-chloro-3-fluorobenzaldehyde (2.61 g, 16.5 mmol) in THF (10 mL) wasadded dropwise. The reaction mixture was stirred for another hour, thenquenched with hydrochloric acid (1.8 mL)/EtOH (7.5 mL)/THF (9.0 mL)mixture, and warmed to rt. The reaction mixture was diluted withsaturated aqueous NaHCO₃ solution and extracted with EtOAc. The organiclayer was separated and washed with brine, dried over Na₂SO₄, filtered,and concentrated under reduced pressure. The residue was purified bysilica gel column chromatography (petroleum ether:EtOAc=4:1) to give thetitle compound as a yellow solid (700 mg, 20%).

MS (ES+) C₁₁H₆Cl₃FN₂O requires: 306, found: 307 [M+H]⁺.

(2-Chloro-3-fluorophenyl)(3,5-dichloropyrazin-2-yl)methanone

To a solution of the product from the previous step (700 mg, 2.3 mmol)in CH₂Cl₂ (200 mL) was added solid MnO₂ (3.99 g, 46.0 mmol) in portions.The resulting mixture was stirred at RT overnight. The reaction mixturewas filtered, and the filtrate was concentrated to give the titlecompound as a yellow solid (650 mg, 93%).

MS (ES+) C₁₁H₄Cl₃FN₂O requires: 304, found: 305 [M+H]⁺. ¹H NMR (500 MHz,DMSO-d₆) δ 8.93 (s, 1H), 7.78-7.67 (m, 1H), 7.61-7.50 (m, 2H).

tert-Butyl(1-(6-chloro-5-(2-chloro-3-fluorobenzoyl)pyrazin-2-yl)-4-hydroxypiperidin-4-yl)methylcarbamate

To a solution of the product from the previous step in DMF (2 mL), underN₂, was added tert-butyl (4-hydroxypiperidin-4-yl)methyl carbamate (57.5mg, 0.25 mmol) and K₂CO₃ (69 mg, 0.5 mmol). The resulting mixture wasstirred overnight at RT and then poured into H₂O (20 mL). The solid wascollected and dried to give the crude title compound as a yellow solid(120 mg), which was used directly without further purification.

MS (ES+) C₂₂H₂₅Cl₂FN₄O₄ requires: 498, found: 499 [M+H]⁺.

tert-Butyl(1-(3-(2-chloro-3-fluorophenyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-4-hydroxypiperidin-4-yl)methylcarbamate

To a solution of the product from the previous step (120 mg, 0.23 mmol)in EtOH (10 mL) was added hydrazine hydrate (23 mg, 0.46 mmol). Theresulting mixture was refluxed under N₂ for 2 h. The solvent was removedto give the crude title compound as a yellow solid (100 mg) which wasused directly without further purification

MS (ES+) C₂₂H₂₆ClFN₆O₃ requires: 476, found: 477 [M+H]⁺.

4-(Aminomethyl)-1-(3-(2-chloro-3-fluorophenyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)piperidin-4-oltrifluoroacetate (37)

To a solution of the crude product from the previous step (100 mg) inCH₂Cl₂ (2 mL) was added TFA (2 mL). The mixture was stirred at rt for 4h, then concentrated under reduced pressure. The residue was purified byPrep-HPLC under acidic condition to give the title compound as a yellowsolid (69.8 mg, 74% over 3 steps).

MS (ES+) C₁₇H₁₈ClFN₆O requires: 376, found: 377 [M+H]⁺. ¹H NMR (400 MHz,DMSO-d₆) δ 13.45 (s, 1H), 8.50 (s, 1H), 7.77 (br, 3H), 7.66-7.64 (m,1H), 7.53-7.50 (m, 2H), 5.20 (s, 1H), 4.21-4.18 (m, 2H), 3.47-3.43 (m,2H), 2.83-2.81 (m, 2H), 1.64-1.62 (m, 4H).

Example 38(S)-8-(3-(2,3-Dichlorophenyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-2-oxa-8-azaspiro[4.5]-decan-4-amine

(3-Chloro-5-((S)-4-((R)-1-(4-methoxyphenyl)ethylamino)-2-oxa-8-azaspiro[4.5]-decan-8-yl)pyrazin-2-yl)(2,3-dichlorophenyl)methanone

To a solution of (2,3-dichlorophenyl)(3,5-dichloropyrazin-2-yl)methanone(80 mg, 0.25 mmol) in DMF (2 mL), under N₂, was added Intermediate 103(72 mg, 0.25 mmol) and K₂CO₃ (69 mg, 0.5 mmol). The resulting mixturewas stirred overnight at RT and then poured into H₂O (20 mL). The solidwas that formed was collected and dried to give the crude title compoundas a yellow solid (120 mg), which was used directly without furtherpurification.

MS (ES+) C₂₈H₂₉Cl₃N₄O₃ requires: 574, found: 575 [M+H]⁺.

(S)-8-(3-(2,3-dichlorophenyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-N—((R)-1-(4-methoxyphenyl)ethyl)-2-oxa-8-azaspiro[4.5]decan-4-amine

To a solution of the crude product from the previous step (120 mg, 0.23mmol) in EtOH (10 mL) was added hydrazine hydrate (23 mg, 0.46 mmol).The resulting mixture was refluxed under N₂ for 2 h. The solvent wasremoved to give the crude title compound as a yellow solid (100 mg)which was used directly without further purification.

MS (ES+) C₂₈H₃₀Cl₂N₆O₂ requires: 552, found: 553 [M+H]⁺.

(S)-8-(3-(2,3-dichlorophenyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-2-oxa-8-azaspiro[4.5]decan-4-amine2,2,2-trifluoroacetate (38)

A mixture of the crude product from the previous step (100 mg) in TFA (2mL) was stirred under microwave at 130° C. for 15 min. The mixture wasconcentrated under reduced pressure. The residue was purified byPrep-HPLC under acidic condition to give the title compound as a lightyellow solid (28 mg, 24% over 3 steps).

MS (ES+) C₁₉H₂₀Cl₂N₆O requires: 418, found: 419 [M+H]⁺. ¹H NMR (500 MHz,DMSO-d6) δ 13.44 (s, 1H), 8.49 (s, 1H), 8.04 (br, 3H), 7.76-7.68 (m,2H), 7.50 (t, J=8.0 Hz, 1H), 4.31-4.21 (m, 2H), 4.11-4.07 (m, 1H),3.88-3.80 (m, 2H), 3.71-3.25 (m, 4H), 1.76-1.62 (m, 4H).

The following Examples were synthesized with synthetic methods that weresimilar to that used for Example 38, and can generally be made bymethods disclosed herein. The Examples may be made as free bases or asTFA salts.

TABLE 6 Examples 39-42. Ex. Name Structure Spectral Data 39(S)-8-(3-(2-chloro- phenyl)-1H- pyrazolo[3,4-b]- pyrazin-6-yl)-2-oxa-8-azaspiro[4.5]- decan-4-amine

MS (ES+)C₁₉H₂₁ClN₆O requires: 384, found: 385 [M + H]⁺. ¹H NMR (500 MHz,DMSO-d₆) δ 13.35 (s, 1H), 8.48 (s, 1H), 8.04 (br, 3H), 7.76-7.74 (m,1H), 7.62-7.60 (m, 1H), 7.48-7.46 (m, 2H), 4.31- 4.21 (m, 2H), 4.11-4.07(m, 1H), 3.88-3.80 (m, 2H), 3.71-3.25 (m, 4H), 1.73-1.62 (m, 4H). 40(4S)-8-(3-(2-Chloro- 6-fluorophenyl)-1H- pyrazolo[3,4-b]-pyrazin-6-yl)-2-oxa- 8-azaspiro[4.5]- decan-4-amine

MS (ES+) C₁₉H₂₀ClFN₆O requires: 402, found: 403 [M + H]⁺. ¹H NMR (500MHz, DMSO-d6) δ 13.48 (s, 1H), 8.45 (s, 1H), 8.01 (br, 3H), 7.59-7.49(m, 2H), 7.39 (t, J = 8.0 Hz, 1H), 4.31-4.21 (m, 2H), 4.11-4.07 (m, 1H),3.88- 3.80 (m, 2H), 3,71-3.25 (m, 4H), 1.73-1.62 (m, 4H). 41(S)-8-(3-(2-chloro- pyridin-3-yl)-1H- pyrazolo[3,4-b]-pyrazin-6-yl)-2-oxa- 8-azaspiro[4.5]- decan-4-amine trifluoroacetate

MS (ES+) C₁₈H₂₀ClN₇O requires: 385, found: 386 [M + H]⁺. ¹H NMR (500MHz, DMSO-d₆) δ 13.52 (s, 1H), 8.52-8.51 (m, 2H), 8.21 (dd, J = 9.5, 2.5Hz, 1H), 8.02 (br, 3H), 7.59 (dd, J = 9.5, 2.5 Hz, 1H), 4.28-4.21 (m,2H), 4.11-4.07 (m, 1H), 3.89- 3.79 (m, 2H), 3.71-3.26 (m, 4H), 1.73-1.61(m, 4H). 42 (S)-8-(3-(2-chloro-3- fluorophenyl)-1H- pyrazolo[3,4-b]-pyrazin-6-yl)-2-oxa- 8-azaspiro[4.5]- decan-4-amine

MS (ES+) C₁₉H₂₀ClFN₆O requires: 402, found: 403 [M + H]⁺. ¹H NMR (500MHz, DMSO-d₆) δ 13.48 (s, 1H), 8.51 (s, 1H), 8.04 (br, 3H), 7.66 (t, J =5.0 Hz, 1H), 7.53-7.49 (m, 2H), 4.31-4.21 (m, 2H), 4.11-4.07 (m, 1H),3.88- 3.80 (m, 2H), 3.71-3.25 (m, 4H), 1.73-1.62 (m, 4H).

Example 43(R)-8-(3-(2,3-Dichlorophenyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-8-azaspiro[4.5]decan-1-amine

(R)-tert-butyl 1-((R)-1-(4-methoxyphenyl)ethylamino)-8-azaspiro[4.5]decane-8-carboxylate

To a solution of tert-butyl 1-oxo-8-azaspiro[4.5]decane-8-carboxylate(2.0 g, 7.9 mmol) in THF (15 mL) was added(R)-1-(4-methoxyphenyl)ethanamine (1.79 g, 11.9 mmol) and Ti(OEt)₄ (2mL) at RT under N₂, then stirred at 85° C. for 18 h. Concentrated invacuo and added MeOH (10 mL) at RT, LiBH₄ (0.33 g, 15.8 mmol) was addedat RT slowly, then stirred at RT for 2 h. Quenched with H₂O (5 mL) andextracted with EtOAc (15 mL×3). The organic layer was separated andwashed with brine, dried over Na₂SO₄, filtered, and concentrated underreduced pressure to give (R)-tert-butyl1-((R)-1-(4-methoxyphenyl)ethylamino)-8-azaspiro[4.5]decane-8-carboxylateas a colorless oil (2.0 g, 66%).

MS (ES+) C₂₃H₃₆N₂O₃ requires: 388, found: 389 [M+H]⁺.

(R)—N—((R)-1-(4-methoxyphenyl)ethyl)-8-azaspiro[4.5]decan-1-amine

A mixture of (R)-tert-butyl1-((R)-1-(4-methoxyphenyl)ethylamino)-8-azaspiro[4.5]decane-8-carboxylate(2.0 g, 5.2 mmol) in HCl/MeOH (3 M, 10 mL) was stirred at RT for 2 h.Concentrated in vacuo and aqueous solution of NaOH was added to adjustthe pH to 10˜12, extracted with EtOAc (15 mL×3). The organic layer wasseparated and washed with brine, dried over Na₂SO₄, filtered, andconcentrated under reduced pressure to give the crude(R)—N—((R)-1-(4-methoxyphenyl)ethyl)-8-aza spiro[4.5] decan-1-amine as acolorless oil (1.2 g, 86%), which was used directly without furtherpurification.

MS (ES+) C₁₈H₂₈N₂O requires: 288, found: 289 [M+H]⁺.

(3-Chloro-5-((R)-1-((R)-1-(4-methoxyphenyl)ethylamino)-8-azaspiro[4.5]decan-8-yl)pyrazin-2-yl)(2,3-dichlorophenyl)methanone

To a solution of (2,3-dichlorophenyl)(3,5-dichloropyrazin-2-yl)methanone(80 mg, 0.25 mmol) in 2 mL DMF, under N₂, was added the product from theprevious step (72 mg, 0.25 mmol) and K₂CO₃ (69 mg, 0.5 mmol). Theresulting mixture was stirred overnight at RT and then poured into H₂O(20 mL). The solid was collected and dried to give the title compound asa yellow solid (114 mg) which was used directly without furtherpurification.

MS (ES+) C₂₉H₃₁Cl₃N₄O₂ requires: 572, found: 573 [M+H]+.

(R)-8-(3-(2,3-dichlorophenyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-N—((R)-1-(4-methoxyphenyl)ethyl)-8-azaspiro[4.5]decan-1-amine

To a solution of the crude product from the previous step (114 mg, 0.2mmol) in EtOH (10 mL) was added hydrazine hydrate (20 mg, 0.4 mmol). Theresulting mixture was refluxed under N₂ for 2 h. The solvent was removedto give the crude the title compound as a yellow solid (100 mg), whichwas used directly without further purification.

MS (ES+) C₂₉H₃₂Cl₂N₆O requires: 550, found: 551 [M+H]⁺.

(R)-8-(3-(2,3-dichlorophenyl)-1H-pyrazolo[3,4-13]pyrazin-6-yl)-8-azaspiro[4.5]decan-1-aminetrifluoroacetate salt (43)

A mixture of the crude product from the previous step (100 mg) in TFA (2mL) was stirred under microwave at 130° C. for 15 min. The mixture wasconcentrated under reduced pressure. The residue was purified byPrep-HPLC under acidic condition to give the titled compound as a lightyellow solid (46.9 mg, 35% over 3 steps).

MS (ES+) C₂₀H₂₂Cl₂N₆ requires: 416, found: 417 [M+H]⁺. ¹H NMR (500 MHz,DMSO-d₆) δ 13.42 (s, 1H), 8.48 (s, 1H), 7.76-7.74 (m, 4H), 7.69 (dd,J=7.5, 1.5 Hz, 1H), 7.50 (t, J=8.0 Hz, 1H), 4.39-4.29 (m, 2H), 3.23-3.14(m, 3H), 2.03-2.01 (m, 1H), 1.86-1.42 (m, 9H).

The following Examples were synthesized with synthetic methods that weresimilar to that used for Example 43, and can generally be made bymethods disclosed herein. The Examples may be made as free bases or asTFA salts.

TABLE 7 Examples 44-56. Ex. Name Structure Spectral Data 44(R)-8-(3-(3-chloro- phenyl)-1H- pyrazolo[3,4-b]- pyrazin-6-yl)-8-aza-spiro[4.5]-decan-1- amine

MS (ES+) C₂₀H₂₃ClN₆ requires: 382, found: 383 [M + H]⁺. ¹H NMR (500 MHz,DMSO-d₆) δ 13.35 (s, 1H), 8.58 (s, 1H), 8.40 (t, J = 2.0 Hz, 1H), 8.27(d, J = 8.0 Hz, 1H), 7.78 (br, 3H), 7.54 (t, J = 8.0 Hz, 1H), 7.46-7.44(m, 1H), 4.40-4.31 (m, 2H), 3.24-3.15 (m, 3H), 2.07- 1.41 (m, 10H). 45(R)-8-(3-(3,5-dichloro- phenyl)-1H- pyrazolo[3,4-b]-pyrazin-6-yl)-8-aza- spiro[4.5]decan-1- amine

MS (ES+) C₂₀H₂₂Cl₂N₆ requires: 416, found: 417 [M + H]⁺. ¹H NMR (500MHz, DMSO-d₆) δ 13.50 (s, 1H), 8.61 (s, 1H), 8.33 (d, J = 1.5 Hz, 2H),7.78 (br, 3H), 7.63 (t, J = 2.0 Hz, 1H), 4.41-4.31 (m, 2H), 3.24-3.14(m, 3H), 2.07-1.38 (m, 10H). 46 (R)-8-(3-(3,4-dichloro- phenyl)-1H-pyrazolo[3,4-b]- pyrazin-6-yl)-8-aza- spiro[4.5]decan-1- amine

MS (ES+) C₂₀H₂₂Cl₂N₆ requires: 416, found: 417 [M + H]⁺. ¹H NMR (500MHz, DMSO-d₆) δ 13.43 (s, 1H), 8.58 (s, 1H), 8.56 (d, J = 2.0 Hz, 111),8.28 (dd, J = 8.0, 2.0 Hz, 1H), 7.82 (br, 3H), 7.78 (d, J = 8.5 Hz, 1H),4.43-4.28 (m, 2H), 3.24-3.15 (m, 3H), 2.10-1.37 (m, 10H). 47(R)-8-(3-(3-chloro-4- fluorophenyl)-1H- pyrazolo[3,4-b]-pyrazin-6-yl)-8-aza- spiro[4.5]decan-1- amine

MS (ES+) C₂₀H₂₂ClFN₆ requires: 400, found: 401 [M + H]⁺. ¹H NMR (500MHz, DMSO-d₆) δ 13.35 (s, 1H), 8.57 (s, 1H), 8.50 (dd, J = 7.5, 2.0 Hz,1H), 8.32-8.28 (m, 1H), 7.78 (br, 3H), 7.57 (t, J = 8.5 Hz, 1H),4.39-4.31 (m, 2H), 3.24-3.15 (m, 2.07-1.41 (m, 10H) 48 (R)-8-(3-(3-(trifluoromethyl)- phenyl)-1H- pyrazolo[3,4- b]pyrazin-6-yl)-8-azaspiro[4.5]decan- 1-amine

MS (ES+) C₂₁H₂₃F₃N₆ requires: 416, found: 417 [M + H]⁺. ^(l)H NMR (500MHz, DMSO-d₆) δ 13.41 (s, 1H), 8.72 (s, 1H), 8.62-8.57 (m, 2H), 7.76-7.74 (m, 5H), 4.41-4.33 (m, 2H), 3.24-3.15 (m, 3H), 2.07-1.41 (m, 10H).49 (R)-8-(3-(3-chloro-2- fluorophenyl)-1H- pyrazolo[3,4-b]-pyrazin-6-yl)-8-aza- spiro[4.5]decan-1- amine

MS (ES+) C₂₀H₂₂ClFN₆ requires: 400, found: 401 [M + H]⁺. ¹H NMR (500MHz, DMSO-d₆) δ 13.48 (s, 1H), 8.53 (s, 1H), 8.11 (t, J = 6.5 Hz, 1H),7.77 (br, 3H), 7.65 (dd, J = 8.5, 1.5 Hz, 1H), 7.38 (t, J = 8.0 Hz, 1H),4.40-4.28 (m, 2H), 3.24-3.14 (m, 3H), 2.07-1.43 (m, 10H). 50(R)-8-(3-(2-chloro-3- methoxyphenyl)-1H- pyrazolo[3,4-b]pyrazin-6-yl)-8- azaspiro[4.5]decan- 1-amine

MS (ES+) C₂₁H₂₅ClN₆O requires: 412, found: 413 [M + H]⁺. ¹H NMR (500MHz, DMSO-d₆) δ 13.29 (s, 1H), 8.45 (s, 1H), 7.73 (br, 3H), 7.41 (d, J =8.0 Hz, 1H), 7.26-7.24 (m, 2H), 4.40-4.28 (m, 2H), 3.92 (s, 3H),3.22-3.13 (m, 3H), 2.06-1.42 (m, 10H). 51 (R)-8-(3-(3-chloro-2-methylphenyl)-1H- pyrazolo[3,4- b]pyrazin-6-yl)-8- azaspiro[4.5]decan-1-amine

MS (ES+) C₂₁H₂₅ClN₆ requires: 396, found: 397 [M + H]⁺. ¹H NMR (500 MHz,DMSO-d₆) δ 13.34 (s, 1H), 8.49 (s, 1H), 7.79 (br, 3H), 7.69 (d, J = 9.0Hz, 1H), 7.52 (dd, J = 10.0, 1.0 Hz, 1H), 7.35 (t, J = 9.5 Hz, 1H),4.40- 4.31 (m, 2H), 3.23-3.12 (m, 3H), 2.47 (s, 3H), 2.07-1.39 (m, 10H).52 (R)-8-(3-(3-chloro-5- methoxyphenyl)-1H- pyrazolo[3,4-b]pyrazin-6-yl)-8- azaspiro[4.5]decan- 1-amine

MS (ES+) C₂₁H₂₅ClN₆O requires: 412, found: 413 [M + H]⁺. ¹H NMR (500MHz, DMSO-d6) δ 13.35 (s, 1H), 8.58 (s, 1H), 7.99 (t, J= 1.5 Hz, 1H),7.84 (t, J= 1.5 Hz, 1H), 7.76 (br, 3H), 7.05 (t, J = 2.0 Hz, 1H),4.40-4.30 (m, 2H), 3.85 (s, 3H), 3.24- 3.14 (m, 3H), 2.09-1.43 (m, 10H).53 (R)-8-(3-(2-chloro- pyridin-3-yl)-1H- pyrazolo[3,4-b]-pyrazin-6-yl)-8- aza- spiro[4.5]decan-1- amine

MS (ES+) C₁₉H₂₂ClN₇ requires: 383, found: 384 [M + H]⁺. ¹H NMR (500 MHz,DMSO-d6) δ 13.48 (s, 1H), 8.52-8.50 (m, 2H), 8.21 (dd, J =7.5, 2.0 Hz,1H), 7.75 (br, 3H), 7.58 (dd, J =8.0, 4.5 Hz, 1H), 4.40-4.32 (m, 2H),3.26-3.13 (m, 3H), 2.06- 1.40 (m, 10H). 54 (R)-8-(3-(2-chlorophenyl)-1H- pyrazolo[3,4-b]- pyrazin-6-yl)-8-aza-spiro[4.5]decan-1- amine

MS (ES+) C₂₀H₂₃ClN₆ requires: 382, found: 383 [M + H]⁺. ¹H NMR (500 MHz,DMSO-d₆) δ 13.33 (s, 1H), 8.47 (s, 1H), 7.76-7.74 (m, 4H), 7.61- 7.59(m, 1H), 7.48-7.46 (m, 2H), 4.40-4.31 (m, 2H), 3.22-3.14 (m, 3H),2.06-1.40 (m, 10H). 55 (R)-8-(3-(2-methyl- pyridin-3-yl)-1H-pyrazolo[3,4-b]- pyrazin-6-yl)-8- azaspiro[4.5]decan- I -amine

MS (ES+) C₂₀H₂₅N₇ requires: 363, found: 364 [M + H]⁺. ¹H NMR (500 MHz,DMSO-d₆) δ 13.57 (s, 1H), 8.72-8.65 (m, 2H), 8.54 (s, 1H), 7.81 (br,3H), 7.68 (t, J = 5.0 Hz, 1H), 4.40-4.32 (m, 2H), 3.25-3.15 (m, 3H),2.85 (s, 3H), 2.04-1.41 (m, 10H). 56 (R)-8-(3-(3-chloro- pyridin-4-yl)-1H- pyrazolo[3,4-b]- pyrazin-6-yl)-8- azaspiro[4.5]decan- 1-amine

MS (ES+) C₁₉H₂₂ClN₇ requires: 383, found: 384 [M + H]⁺. ¹H NMR (500 MHz,DMSO-d₆) δ 13.66 (s, 1H), 8.78 (s, 1H), 8.65 (d, J =5.0 Hz, 1H), 8.56(s, 1H), 8.03 (d, J = 5.0 Hz, 1H), 7.76 (br, 3H), 4.40-4.32 (m, 2H),3.24- 3.14 (m, 3H), 2.08-1.43 (m, 10H).

Example 57(4-Amino-1-(3-(2,3-dichlorophenyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)piperidin-4-yl)-methanol

Benzyl1-(6-chloro-5-(2,3-dichlorobenzoyl)pyrazin-2-yl)-4-(hydroxymethyl)-piperidin-4-ylcarbamate

To a solution of (2,3-dichlorophenyl)(3,5-dichloropyrazin-2-yl)methanone(80 mg, 0.25 mmol) in 2 mL DMF, under N₂, was added Intermediate 104 (75mg, 0.25 mmol) and K₂CO₃ (69 mg, 0.5 mmol). The resulting mixture wasstirred overnight at RT and then poured into H₂O (20 mL). The solid wascollected and dried to give the crude title compound as a yellow solid(126 mg) which was used directly without further purification.

MS (ES+) C₂₅H₂₃Cl₃N₄O₄ requires: 548, found: 549 [M+H]⁺.

Benzyl1-(3-(2,3-dichlorophenyl)-1H-pyrazolo[3,4-13]pyrazin-6-yl)-4-(hydroxymethyl)piperidin-4-ylcarbamate

To a solution of the crude product from the previous step (126 mg, 0.23mmol) in EtOH (10 mL) was added hydrazine hydrate (23 mg, 0.46 mmol).The resulting mixture was refluxed under N₂ for 2 h. The solvent wasremoved to give the crude title product as a yellow solid (100 mg),which was used directly without further purification.

MS (ES+) C₂₅H₂₄Cl₂N₆O₃ requires: 526, found: 527 [M+H]⁺.

(4-Amino-1-(3-(2,3-dichlorophenyl)-1H-pyrazolo[3,4-13]pyrazin-6-yl)piperidin-4-yl)methanoltrifluoroacetate (57)

A mixture of the crude product from the previous step (100 mg) in TFA (2mL) was stirred under microwave at 130° C. for 15 min. The mixture wasconcentrated under reduced pressure. The residue was purified byPrep-HPLC under acidic condition to give the title compound as a lightyellow solid (21.6 mg, 17% over 3 steps).

MS (ES+) C₁₇H₁₈Cl₂N₆O requires: 392, found: 393 [M+H]⁺. ¹H NMR (500 MHz,DMSO-d₆) δ 13.47 (s, 1H), 8.48 (s, 1H), 7.88 (br, 3H), 7.76 (dd, J=8.0,1.5 Hz, 1H), 7.69 (dd, J=8.0, 1.5 Hz, 1H), 7.50 (t, J=8.0 Hz, 1H), 5.59(s, 1H), 4.10-4.04 (m, 2H), 3.63-3.55 (m, 4H), 1.88-1.72 (m, 4H).

The following Examples were synthesized with synthetic methods that weresimilar to that used for Example 57, and can generally be made bymethods disclosed herein. The Examples may be made as free bases or asTFA salts.

TABLE 8 Examples 58-63. Name Structure Spectral Data 581-(3-(2,3-dichlo- rophenyl)-1H- pyrazolo[3,4-b]- pyrazin-6-yl)-4-(fluoromethyl)- piperidin-4-amine

MS (ES+) C₁₇H₁₇Cl₂N₆ requires: 394, found: 395 [M + H]⁺. ¹H NMR (500MHz, DMSO-d₆) δ 13.48 (s, 1H), 8.52 (s, 1H), 8.07 (br, 3H), 7.76 (dd, J= 8.0, 1.5 Hz, 1H), 7.69 (dd, J = 8.0, 1.5 Hz, 1H), 7.50 (t, J = 8.0 Hz,1H), 4.40-4.37 (m, 2H), 3.36- 3.13 (m, 4H), 1.99-1.79 (m, 4H). 59(4-amino-1-(3-(2- chloropyridin-3-yl)- 1H-pyrazolo[3,4- b]pyrazin-6-yl)-piperidin-4-yl)- methanol

MS (ES+) C₁₆H₁₈ClN₇O requires: 359, found: 360 [M + H]⁺. ¹H NMR (500MHz, DMSO-d₆) δ 13.55 (s, 1H), 8.52-8.51 (m, 2H), 8.21 (dd, J = 7.5, 2.0Hz, 1H), 7.89 (br, 3H), 7.58 (dd, J = 7.5, 4.5 Hz, 1H), 5.60 (s, 1H),4.08- 4.04 (m, 2H), 3.64-3.56 (m, 4H), 1.88-1.70 (m, 4H). 604-(aminomethyl)-1- (3-(2-chlorophenyl)- 1H-pyrazolo[3,4-b]-pyrazin-6-yl)- piperidin-4-ol

MS (ES+) C₁₇H₁₉ClN₆O requires: 358, found: 359 [M + H]⁺. ¹H NMR (500MHz, DMSO-d₆) δ 13.33 (s, 1H), 8.47 (s, 1H), 7.80-7.74 (m, 4H), 7.61-7.59 (m, 1H), 7.48-7.46 (m, 2H), 5.20 (s, 1H), 4.20-4.17 (m, 2H), 3.48-3.43 (m, 2H), 2.83-2.81 (m, 2H), 1.65-1.62 (m, 4H). 61 (4-amino-1-(3-(2-chlorophenyl)-1H- pyrazolo[3,4-b]- pyrazin-6-yl)- piperidin-4-yl)-methanol

MS (ES+) C₁₇H₁₈ClN₆O requires: 358, found: 359 [M + H]⁺. ¹H NMR (500MHz, DMSO-d₆) δ 13.41 (s, 1H), 8.48 (s, 1H), 7.89 (br, 3H), 7.76-7.73(m, 1H), 7.62-7.60 (m, 1H), 7.49-7.47 (m, 2H), 5.61 (s, 1H), 4.07-4.03(m, 2H), 3.63-3.54 (m, 4H), 1.88-1.70 (m, 4H). 62 (4-amino-1-(3-(2-chloro-3-fluoro- phenyl)-1H- pyrazolo[3,4-b]- pyrazin-6-yl)-piperidin-4-yl)- methanol

MS (ES+) C₁₇H₁₈ClFN₆O requires: 376, found: 377 [M + H]⁺. ¹H NMR (500MHz, DMSO-d₆) δ 13.51 (s, 1H), 8.50 (s, 1H), 7.88 (br, 3H), 7.67-7.65(m, 1H), 7.53-7.51 (m, 2H), 5.60 (t, 1H), 4.07-4.04 (m, 2H), 3.64-3.58(m, 4H), 1.88-1.72 (m, 4H). 63 4-(aminomethyl)-1- (3-(2-chloro-6-fluorophenyl)-1H- pyrazolo [3,4-b]- pyrazin-6-yl)- piperidin-4-ol

MS (ES+) C₁₇H₁₈ClFN₆O requires: 376, found: 377 [M + H]⁺. ¹H NMR (500MHz, DMSO-d₆) δ 13.46 (s, 1H), 8.44 (s, 1H), 7.76 (br, 3H), 7.58-7.49(m, 2H), 7.38 (t, J = 8.5 Hz, 1H), 5.19 (s, 1H), 4.20- 4.17 (m, 2H),3.48-3.43 (m, 2H), 2.82 (d, J = 5.5 Hz, 2H), 1.65-1.62 (m, 4H).

Example 64A/B8-(3-(2,3-Dichlorophenyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-2-fluoro-8-azaspiro[4.5]decan-1-aminediastereomers A and B

Benzyl 1-oxo-8-azaspiro[4.5]decane-8-carboxylate

To a mixture of 8-azaspiro[4.5]decan-1-one (1 g, crude) in CH₂Cl₂ (10mL) was added TEA (1.6 g, 15.8 mmol) and CbzOSu (1.18 g, 4.3 mmol) at 0°C. The mixture was stirred at room temperature for 2 hours. The mixturewas diluted with CH₂Cl₂ (10 mL). The organic layers were washed withNH₄Cl (10 mL×2) and brine (10 mL), dried with MgSO₄, concentrated andpurified by column silica gel (petroleum ether:EtOAc=10:1-1:1) to obtainthe title compound as a white solid (940 mg, 83%).

MS (ES+) C₁₇H₂₁NO₃ requires: 287, found: 288 [M+H]⁺.

Benzyl 2-fluoro-1-oxo-8-azaspiro[4.5]decane-8-carboxylate

In 15 mL H₂O was combined the product from the previous step (940 mg,3.3 mmol), SELECTFLUOR™ (1.3 g, 3.63 mmol), and sodium dodecyl sulfate(0.8 g). The mixture was purged with N₂ and stirred at 80° C. for 48hours. The mixture was extracted with EtOAc (20 mL×3). The organic phasewas dried with Na₂SO₄, concentrated and purified by column silica gel(petroleum ether:EtOAc=20:1-4:1) to obtain the title compound as a whitesolid (500 mg).

MS (ES+) C₁₇H₂₀FNO₃ requires: 305, found: 306 [M+H]⁺.

(Z)-Benzyl-1-(tert-butylsulfinylimino)-2-fluoro-8-azaspiro[4.5]decane-8-carboxylate

To a solution of the product from the previous step (500 mg, 1.6 mmol)in THF (8 mL, dry) was added 2-methylpropane-2-sulfinamide (581 mg, 4.8mmol) and Ti(OEt)₄ (2 mL). The mixture was stirred at 80° C. overnight.The mixture was concentrated and used directly for the next step.

MS (ES+) C₂₁₁₁₂₉FN₂O₃S requires: 408, found: 409 [M+H]⁺.

Benzyl 1-(1,1-dimethylethylsulfinamido)-2-fluoro-8-azaspiro[4.5]decane-8-carboxylate

To a mixture of the crude product from the previous step (2 g, crude) inMeOH (10 mL) was added LiBH₄ (105 mg, 4.8 mmol) at 0° C. The mixture wasstirred at RT for 2 hours, then quenched with H₂O (10 mL) andconcentrated. EtOAc (20 mL) was added, and the residue was filteredthrough a short CELITE™ column. The water phase was extracted with EtOAc(20 mL×3). The organic phases were combined and washed with brine (20mL), dried with MgSO₄, concentrated and purified by Pre-HPLC to obtainthe title compound as a white solid (isomer A: 200 mg, isomer B: 120mg).

MS (ES+) C₂₁H₃₁FN₂O₃S requires: 410, found: 411 [M+H]⁺.

N-(2-fluoro-8-azaspiro[4.5]decan-1-yl)-2-methylpropane-2-sulfinamide,isomer A

To a solution of isomer A of the compound from the previous step (150mg) in MeOH (5 mL) was added Pd/C (10%, 30 mg), and Boc₂O (0.4 mL). Themixture was filled with H₂ and stirred at RT under H₂ for 1 hour. Thesolids were removed by filtration. The resulting solution wasconcentrated. The residue was dissolved in CH₂Cl₂ (10 mL), TFA (2 mL)was added slowly at 0° C., and the resulting mixture was stirred at thistemperature for 30 min. The reaction was monitored with LCMS until allof the starting material was consumed. At this point, the residue wasconcentrated and used directly for the next step.

MS (ES+) C₁₃H₂₅FN₂OS requires: 276, found: 277 [M+H]⁺.

A similar procedure was used for isomer B.

N-(8-(6-chloro-5-(2,3-dichlorobenzoyl)pyrazin-2-yl)-2-fluoro-8-azaspiro-[4.5]decan-1-yl)-2-methylpropane-2-sulfinamide,isomer A

To a mixture of the product from the previous step (300 mg, crude) inDMF (5 mL) was added(2,3-dichlorophenyl)(3,5-dichloropyrazin-2-yl)methanone (120 mg) andK₂CO₃ (300 mg). The mixture was stirred at RT for 2 hours. H₂O (20 mL)was added, and the mixture was extracted with EtOAc (20 mL×3). Theorganic phases were combined and washed with brine (20 mL) andconcentrated to obtain the title compound as brown oil (500 mg).

MS (ES+) C₂₄H₂₈Cl₃FN₄O₂S requires 562, found 563 [M+H]⁺.

A similar procedure was used for isomer B.

N-(8-(3-(2,3-dichlorophenyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-2-fluoro-8-azaspiro[4.5]decan-1-yl)-2-methylpropane-2-sulfinamide,isomer A

To a solution of the product from the previous step (500 mg, crude) inEtOH (10 mL) was added NH₂NH₂ (98%, 0.5 mL). The mixture was stirred at80° C. for 2 hours, then concentrated to obtain the title compound as abrown solid (600 mg, crude).

MS (ES+) C₂₄H₂₉Cl₂FN₆OS requires 538, found 539 [M+H]⁺.

A similar procedure was used for isomer B.

8-(3-(2,3-Dichlorophenyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-2-fluoro-8-azaspiro[4.5]decan-1-amine,isomer A(64A)

A solution of the product from the previous step (600 mg, crude) in 4 MHCl/dioxane (10 mL) was stirred at 50° C. for 1 hour. The mixture wasconcentrated and dissolved in DMF, purified by Pre-HPLC to obtain thetitle compound as a light yellow solid (isomer 1: 42 mg).

Isomer A: MS (ES+) C₂₀H₂₁Cl₂FN₆ requires: 435, found: 436 [M+H]⁺; ¹H NMR(400 MHz, DMSO-d₆) δ 13.39 (s, 1H), 8.44 (s, 1H), 7.75 (dd, J=8.0, 1.5Hz, 1H), 7.70 (dd, J=7.7, 1.5 Hz, 1H), 7.49 (t, J=7.9 Hz, 1H), 4.84 (dd,J=59.9, 4.0 Hz, 1H), 4.41 (d, J=13.5 Hz, 2H), 3.11 (dt, J=23.3, 15.0 Hz,2H), 2.58 (dd, J=32.0, 4.0 Hz, 1H), 2.24-0.87 (m, 10H). ¹⁹F NMR (376MHz, DMSO-d₆) δ −184.34 (s).

A similar procedure was used for isomer B.

Isomer B: (33 mg): MS (ES+) C₂₀H₂₁Cl₂FN₆ requires: 435, found: 436[M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 13.39 (s, 1H), 8.44 (s, 1H), 7.75(dd, J=8.0, 1.5 Hz, 1H), 7.70 (dd, J=7.7, 1.5 Hz, 1H), 7.49 (t, J=7.9Hz, 1H), 4.84 (dd, J=59.9, 4.0 Hz, 1H), 4.41 (d, J=13.0 Hz, 2H),3.24-2.94 (m, 2H), 2.58 (dd, J=32.4, 3.5 Hz, 1H), 2.20-0.87 (m, 10H).¹⁹F NMR (376 MHz, DMSO-d₆) δ −184.34 (s).

Example 65A/B8-(3-(2,3-Dichlorophenyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-2,2-difluoro-8-azaspiro[4.5]decan-1-amine,enantiomers A and B

tert-Butyl 2,2-difluoro-1-oxo-8-azaspiro[4.5]decane-8-carboxylate

To a solution of NaHMDS (2 M in THF, 21.7 mL, 43.4 mmol) was added asolution of tert-butyl 1-oxo-8-azaspiro[4.5]decane-8-carboxylate (10.0g, 39.5 mmol) in THF (25 mL) at −78° C. After stirring for 30 min atthis temperature, a solution of N-fluorobenzenesulfonamide (12.5 g, 39.5mmol) in THF (50 mL) was added. After 3 hours stirring at −78° C., thesolution was diluted with sat. aq NaHCO₃ (200 mL) and extracted withCH₂Cl₂ (3×200 mL). The combined organic phases was washed with brine,dried over MgSO₄, filtered, and concentrated under reduced pressure. Theresulting residue was purified by silica chromatography (0 to 5 percentgradient of MeOH/CH₂Cl₂) to obtain the title compound as a white solid(800 mg, 7.3%).

MS (ES+) C₁₄H₂₁F₂NO₃ requires: 289, found: 234 [M+H-56]⁺.

(R,Z)-tert-butyl1-(tert-butylsulfinylimino)-2,2-difluoro-8-azaspiro[4.5]decane-8-carboxylate

To a solution of the product from the previous step (800 mg, 2.7 mmol)in THF (10 mL, dry) was added 2-methylpropane-2-sulfinamide (1.0 g, 8.3mmol) and Ti(OEt)₄ (2 mL). The mixture was stirred at 80° C. overnight.The mixture was concentrated and used directly for the next step.

MS (ES+) C₁₈H₃₀F₂N₂O₃S requires: 392, found: 293 [M+H-100]⁺.

(S)-tert-butyl1-((R)-1,1-dimethylethylsulfinamido)-2,2-difluoro-8-azaspiro-[4.5]decane-8-carboxylate

To a mixture of the product from the previous step (2 g, crude) in MeOH(10 mL) was added LiBH₄ (180 mg, 8.1 mmol) at 0° C. The resultingmixture was stirred at RT for 2 hours. The mixture was quenched with H₂O(10 mL), and concentrated. EtOAc (20 mL) was added, and the resultingsolution was filtered through a short CELITE™ column. The aqueous phasewas extracted with EtOAc (20 mL×3). The combined organic phases werewashed with brine (20 mL), dried with MgSO₄, concentrated and purifiedby Pre-HPLC to obtain the title compound as a white solid (isomer A: 450mg, isomer B: 330 mg).

MS (ES+) C₁₈H₃₂F₂N₂O₃S requires: 394, found: 295 [M+H-100]⁺.

(R)—N-(2,2-difluoro-8-azaspiro[4.5]decan-1-yl)-2-methylpropane-2sulfinamide, isomer A

To a solution of isomer A of the crude product from the previous step(isomer 1: 150 mg) in CH₂Cl₂ (10 mL) was added TFA (2 mL) slowly at 0°C. The mixture was stirred at this temperature for 30 min, thenconcentrated and used directly for the next step.

MS (ES+) C₁₃H₂₄F₂N₂OS requires: 294, found: 295 [M+H]+.

A similar procedure was used for isomer B.

(R)—N-(8-(6-chloro-5-(2,3-dichlorobenzoyl)pyrazin-2-yl)-2,2-difluoro-8-azaspiro-[4.5]decan-1-yl)-2-methylpropane-2-sulfinamide,isomer A

To a mixture of the product from the previous step (300 mg, crude) inDMF (5 mL) was added(2,3-dichlorophenyl)(3,5-dichloropyrazin-2-yl)methanone (120 mg) andK₂CO₃ (300 mg). The mixture was stirred at RT for 2 hours. H₂O (20 mL)was added, and the mixture was extracted with EA (20 mL×3). The combinedorganic phases was washed with brine (20 mL) and concentrated to obtainthe title compound as brown oil (500 mg, crude).

MS (ES+) C₂₄H₂₇Cl₃F₂N₄O₂S requires: 578, found: 579 [M+H]⁺.

A similar procedure was used for isomer B.

(R)—N-(8-(3-(2,3-dichlorophenyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-2,2-difluoro-8-azaspiro[4.5]decan-1-yl)-2-methylpropane-2-sulfinamide,isomer A

To a solution of the product from the previous step o (isomer 1: 500 mg,crude) in EtOH (10 mL) was added NH₂NH₂ (98%, 0.5 mL). The mixture wasstirred at 80° C. for 2 hours, then concentrated to obtain the titlecompound as a brown solid (600 mg, crude).

MS (ES+) C₂₄H₂₈Cl₂F₂N₆OS requires: 556, found: 557 [M+H]⁺.

A similar procedure was used for isomer B.

8-(3-(2,3-Dichlorophenyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-2,2-difluoro-8-azaspiro[4.5]decan-1-amine,isomer A(65A)

A solution of the product from the previous step (600 mg, crude) in 4 MHCl/dioxane (10 mL) was stirred at 50° C. for 1 hour. The mixture wasconcentrated and dissolved in DMF purified by Pre-HPLC to obtain thetitle compound as a light yellow solid (isomer 1: 70 mg; isomer 2: 49mg).

Isomer A: MS (ES+) C₂₀H₂₀Cl₂F₂N₆ requires: 453, found: 454 [M+H]⁺; ¹HNMR (400 MHz, DMSO-d₆) δ 13.40 (s, 1H), 8.45 (s, 1H), 7.75 (dd, J=8.0,1.5 Hz, 1H), 7.70 (dd, J=7.7, 1.5 Hz, 1H), 7.49 (t, J=7.9 Hz, 1H), 4.37(d, J=10.5 Hz, 2H), 3.24-2.99 (m, 2H), 2.83 (dd, J=18.0, 13.0 Hz, 1H),2.27-1.08 (m, 10H). ¹⁹F NMR (376 MHz, DMSO-d₆) δ −97.16 (d, J=226.1 Hz),−99.39 (d, J=226.0 Hz).

A similar procedure was used for isomer B.

Isomer B: MS (ES+) C₂₀H₂₀Cl₂F₂N₆ requires: 453, found: 454 [M+H]⁺; ¹HNMR (400 MHz, DMSO-d₆) δ 13.40 (s, 1H), 8.44 (s, 1H), 7.74 (d, J=8.0 Hz,1H), 7.70 (d, J=7.7 Hz, 1H), 7.49 (t, J=7.9 Hz, 1H), 4.37 (d, J=12.6 Hz,2H), 3.14 (dt, J=23.5, 11.8 Hz, 2H), 2.95-2.70 (m, 1H), 2.30-0.99 (m,10H). ¹⁹F NMR (376 MHz, DMSO-d₆) δ −97.20 (d, J=226.1 Hz), −99.44 (d,J=226.0 Hz).

Example 1014-Methyl-1-(3-(5-(trifluoromethyl)-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-piperidin-4-amine

tert-Butyl 1-(6-chloro-5-(5-(trifluoromethyl)-1H-pyrazole-4-carbonyl)pyrazin-2-yl)-4-methylpiperidin-4-yl carbamate

To a solution of(3,5-dichloropyrazin-2-yl)(5-(trifluoromethyl)-1H-pyrazol-4-yl)methanone(62.2 mg, 0.2 mmol) in DMF (2 mL) under N₂ was added tert-butyl4-methylpiperidin-4-yl carbamate (42.8 mg, 0.2 mmol) and K₂CO₃ (55.3 mg,0.4 mmol). The result mixture was stirred overnight at RT and pouredinto H₂O (20 mL). The solid that formed was removed by filtration anddried to give the crude title compound as a yellow solid (120 mg) whichwas used directly without further purification.

MS (ES+) C₂₀H₂₄ClF₃N₆O₃ requires: 488, found: 489 [M+H]+.

tert-Butyl4-methyl-1-(3-(5-(trifluoromethyl)-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)piperidin-4-ylcarbamate

To a solution of the crude product from the previous step (120 mg, 0.24mmol) in EtOH (10 mL) was added hydrazine hydrate (23 mg, 0.46 mmol).The resulting mixture was refluxed under N₂ for 2 h. The solvent wasremoved to give the crude title compound as a yellow solid (100 mg)which was used directly without further purification.

MS (ES+) C₂₀H₂₅F₃N₈O₂ requires: 466, found: 467[M+H]+.

4-Methyl-1-(3-(5-(trifluoromethyl)-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)piperidin-4-amine

A solution of the product from the previous step (100 mg, 0.21 mmol) inTFA (5 mL) was stirred at RT for 5 h, then concentrated under reducedpressure. The residue was purified by Prep-HPLC to give the titlecompound as a yellow solid (31.2 mg, yield 42%).

MS (ES+) C₁₅H₁₇F₃N₈ requires: 366, found: 367 [M+H]+. 1H NMR (500 MHz,DMSO) δ 13.86 (s, 1H), 13.24 (s, 1H), 8.57 (s, 1H), 8.49 (s, 1H), 7.94(s, 3H), 4.16 (s, 2H), 3.46 (s, 2H), 1.77 (s, 4H), 1.40 (s, 3H).

Example 102(R)-8-(3-(5-(Trifluoromethyl)-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-8-azaspiro[4.5]decan-1-amine

(3-Chloro-5-((1R)-1-(1-(4-methoxyphenyl)ethylamino)-8-azaspiro[4.5]decan-8-yl)pyrazin-2-yl)(5-(trifluoromethyl)-1H-pyrazol-4-yl)methanone

To a solution of(3,5-dichloropyrazin-2-yl)(5-(trifluoromethyl)-1H-pyrazol-4-yl)methanone(62.2 mg, 0.2 mmol) in DMF (2 mL) under N₂ was added(1R)—N-(1-(4-methoxyphenyl)ethyl)-8-azaspiro[4.5]decan-1-amine (57.6 mg,0.2 mmol) and K₂CO₃ (55.3 mg, 0.4 mmol). The result mixture was stirredovernight at RT, then poured into H₂O (20 mL). The solid that formed wasremoved by filtration and dried to give the crude title compound as ayellow solid (120 mg) which was used directly without furtherpurification.

MS (ES+) C₂₇H₃₀ClF₃N₆O₂ requires: 562, found: 563 [M+H]+.

(1R)—N-(1-(4-methoxyphenyl)ethyl)-8-(3-(5-(trifluoromethyl)-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-8-azaspiro[4.5]decan-1-amine

To a solution of the crude product from the previous step (120 mg, 0.21mmol) in EtOH (10 mL) was added hydrazine hydrate (23 mg, 0.46 mmol).The result mixture was refluxed under N₂ for 2 h. The solvent wasremoved to give the crude title compound as a yellow solid (100 mg)which was used directly without further purification.

MS (ES+) C₂₇H₃₁F₃N₈O requires: 540, found: 541[M+H]+.

(R)-8-(3-(5-(Trifluoromethyl)-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-8-azaspiro[4.5]decan-1-amine

A solution of the product from the previous step (100 mg, 0.18 mmol) inTFA (5 mL) was stirred at 120° C. for 0.5 h under microwave irradiation,then concentrated under reduced pressure. The residue was purified byPrep-HPLC to give the titled compound as yellow solid (13.4 mg, yield16%).

MS (ES+) C₁₈H₂₁F₃N₈ requires: 406, found: 407 [M+H]+. 1H NMR (500 MHz,DMSO) δ 13.85 (s, 1H), 13.17 (s, 1H), 8.56 (s, 1H), 8.48 (s, 1H), 7.77(s, 3H), 4.35 (dd, J=28.1, 13.5 Hz, 2H), 3.16 (dd, J=18.2, 10.1 Hz, 3H),2.06 (s, 1H), 1.85-1.42 (m, 9H).

Example 103(R)-8-(3-(5-(Trifluoromethyl)-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-8-azaspiro[4.5]decan-1-amine

tert-Butyl(1-(6-chloro-5-(5-(trifluoromethyl)-1H-pyrazole-4-carbonyl)pyrazine-2-yl)-4-methylpiperidin-4-yl)methylcarbamate

To a solution of(3,5-dichloropyrazin-2-yl)(5-(trifluoromethyl)-1H-pyrazol-4-yl)methanone(62.2 mg, 0.2 mmol) in 2 mL DMF under Na was added tert-butyl(4-methylpiperidin-4-yl)methyl carbamate (45.6 mg, 0.2 mmol) and K₂CO₃(55.3 mg, 0.4 mmol). The resulting mixture was stirred overnight at RTand poured into H₂O (20 mL). The solid that formed was removed byfiltration and dried to give the crude title compound crude as a yellowsolid (120 mg) which was used directly without further purification.

MS (ES+) C₂₁H₂₆ClF₃N₆O₃ requires: 502, found: 503 [M+H]+.

tert-Butyl(4-methyl-1-(3-(5-(trifluoromethyl)-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)piperidin-4-yl)methylcarbamate

To a solution of the crude product from the previous step (120 mg, 0.24mmol) in EtOH (10 mL) was added hydrazine hydrate (23 mg, 0.46 mmol).The resulting mixture was refluxed under N₂ for 2 h. The solvent wasremoved to give the crude title compound as a yellow solid (100 mg)which was used directly without further purification.

MS (ES+) C₂₁H₂₇F₃N₈O₂ requires: 480, found: 481[M+H]+.

(4-Methyl-1-(3-(5-(trifluoromethyl)-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-b]-pyrazine-6-yl)piperidin-4-yl)methanamine

A solution of the product from the previous step (100 mg, 0.2 mmol) inTFA (5 mL) was stirred at RT for 4 h, then concentrated under reducedpressure. The residue was purified by Prep-HPLC to give the titlecompound as yellow solid (25.3 mg, yield 32%).

MS (ES+) C₁₆H₁₉F₃N₈ requires: 380, found: 381 [M+H]+. 1H NMR (500 MHz,DMSO) δ 13.83 (s, 1H), 13.14 (s, 1H), 8.55 (s, 1H), 8.46 (s, 1H), 7.70(s, 3H), 4.02 (d, J=15.0 Hz, 2H), 3.49 (d, J=9.9 Hz, 2H), 2.80 (d, J=5.6Hz, 2H), 1.55 (d, J=9.7 Hz, 2H), 1.46 (s, 2H), 1.09 (s, 3H).

Example 1044-(6-(4-(Aminomethyl)-4-methylpiperidin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-3-yl)-3-chloro-N-methylpyridin-2-amine

tert-Butyl(1-(6-chloro-5-(3-chloro-2-(methylamino)isonicotinoyl)pyrazine-2-yl)-4-methylpiperidin-4-yl)methylcarbamate

To a solution of Intermediate 113 (63.2 mg, 0.2 mmol) in DMF (2 mL)under N₂ was added tert-butyl (4-methylpiperidin-4-yl)methyl carbamate(45.6 mg, 0.2 mmol) and K₂CO₃ (55.3 mg, 0.4 mmol). The resulting mixturewas stirred overnight at RT and poured into H₂O (20 mL). The solid thatformed was removed by filtration and dried to give the title compound asa yellow solid (120 mg) which was used directly without furtherpurification.

MS (ES+) C₂₃H₃₀C₁₂N₆O₃ requires: 508, found: 509 [M+H]+.

tert-Butyl (1-(3-(3-chloro-2-(methylamino)pyridin-4-yl)-1H-pyrazolo[3,4-b]-pyrazin-6-yl)-4-methylpiperidin-4-yl)methyl carbamate

To a solution of the crude product from the previous step (120 mg, 0.24mmol) in EtOH (10 mL) was added hydrazine hydrate (23 mg, 0.46 mmol).The resulting mixture was refluxed under N₂ for 2 h. The solvent wasremoved to give the crude title compound crude as a yellow solid (100mg) which was used directly without further purification.

MS (ES+) C₂₃H₃₁ClN₈O₂ requires: 486, found: 487[M+H]+.

4-(6-(4-(Aminomethyl)-4-methylpiperidin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-3-yl)-3-chloro-N-methylpyridin-2-amine

A solution of the product from the previous step (100 mg, 0.21 mmol) inTFA (5 mL) was stirred at RT for 2 h, then concentrated under reducedpressure. The residue was purified by Prep-HPLC to give the titlecompound as yellow solid (50 mg, yield 65%).

MS (ES+) C₁₈H₂₃ClN₈ requires: 386, found: 387 [M+H]+. 1H NMR (500 MHz,DMSO) δ 13.49 (s, 1H), 8.49 (s, 1H), 8.08 (d, J=5.2 Hz, 1H), 7.74 (s,3H), 7.02 (d, J=5.1 Hz, 1H), 6.87 (s, 1H), 4.04-4.00 (m, 2H), 3.51 (t,J=10.1 Hz, 2H), 2.93 (s, 3H), 2.80 (d, J=6.0 Hz, 2H), 1.56 (dd, J=16.2,6.6 Hz, 2H), 1.46 (d, J=13.8 Hz, 2H), 1.09 (s, 3H).

Example 1051-(3-(3-amino-2-chlorophenyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-4-methylpiperidin-4-amine

tert-Butyl1-(5-(3-amino-2-chlorobenzoyl)-6-chloropyrazin-2-yl)-4-methylpiperidin-4-ylcarbamate

To a solution of Intermediate 112 (30 mg, 0.1 mmol) in DMF (3 mL) underN₂, was added tert-butyl 4-methylpiperidin-4-yl carbamate (21 mg, 0.1mmol) and K₂CO₃ (27 mg, 0.2 mmol). The resulting mixture was stirred atRT for 4 h and then poured into H₂O (20 mL). The mixture was extractedwith EtOAc (20 mL×3). The combined organic layers were washed withbrine, dried over Na₂SO₄ and concentrated to give the crude titlecompound (43 mg), which was used directly without further purification.

MS (ES+) C₂₂H₂₇Cl₂N₅O₃ requires: 479, found: 480.2 [M+H]+.

tert-Butyl1-(3-(3-amino-2-chlorophenyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-4-methylpiperidin-4-ylcarbamate

To a solution of the crude product from the previous step (43 mg, 0.09mmol) in EtOH (10 mL) was added hydrazine hydrate (9 mg, 0.18 mmol). Theresulting mixture was refluxed under N₂ overnight. The solvent wasremoved to give the title compound as a yellow solid (35 mg) which wasused directly without further purification.

MS (ES+) C₂₂H₂₈ClN₇O₂ requires: 457, found: 458.2 [M+H]+.

1-(3-(3-Amino-2-chlorophenyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-4-methylpiperidin-4-aminetrifluoroacetate

A mixture of the crude product from the previous step (35 mg) in TFA (2mL) and DCM (2 mL) was stirred at RT for 4 h. The mixture wasconcentrated under reduced pressure. The residue was purified byPrep-HPLC under acidic conditions to give the title compound as a lightyellow solid (15.4 mg, 33% over 3 steps).

MS (ES+) C₁₉H₂₁ClF₃N₇O₂ requires: 357, found: 358.2 [M+H]+. ¹H NMR (500MHz, DMSO-d₆) δ 13.29 (s, 1H), 8.44 (s, 1H), 7.98 (br, 3H), 7.11 (t,J=10.0 Hz, 1H), 6.89 (dd, J=2.0, 10.0 Hz, 1H), 6.82 (dd, J=2.0, 10.0 Hz,1H), 4.19-4.16 (m, 2H), 3.48-3.41 (m, 2H), 1.78-1.76 (m, 4H), 1.40 (s,3H).

Example 1064-(6-(4-Amino-4-methylpiperidin-1-yl)-1H-pyrazolo[3,4-b]pyrazine-3-yl)-3-chloropyridin-2-amine

tert-Butyl1-(6-chloro-5-(3-chloro-2-(4-methoxybenzylamino)isonicotinoyl)-pyrazin-2-yl)-4-methylpiperidin-4-ylcarbamate

To a solution of Intermediate 108 (84 mg, 0.2 mmol) in DMF (5 mL), underN₂, was added tert-butyl 4-methylpiperidin-4-yl carbamate (43 mg, 0.2mmol) and K₂CO₃ (55 mg, 0.4 mmol). The resulting mixture was stirred atRT for 4 h and then poured into H₂O (20 mL). The mixture was extractedwith EtOAc (20 mL×3). The combined organic layers were washed withbrine, dried over Na₂SO₄ and concentrated to give the crude titlecompound (108 mg), which was used directly without further purification.

MS (ES+) C₂₉H₃₄Cl₂N₆O₄ requires: 600, found: 601.2 [M+H]+.

tert-Butyl1-(3-(3-chloro-2-(4-methoxybenzylamino)pyridin-4-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-4-methylpiperidin-4-ylcarbamate

To a solution of the crude product from the previous step (108 mg, 0.18mmol) in EtOH (10 mL) was added hydrazine hydrate (18 mg, 0.36 mmol).The resulting mixture was refluxed under N₂ overnight. The solvent wasremoved to give the title compound as a yellow solid (90 mg) which wasused directly without further purification.

MS (ES+) C₂₉H₃₅ClN₈O₃ requires: 578, found: 579.2 [M+H]+.

4-(6-(4-Amino-4-methylpiperidin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-3-yl)-3-chloropyridin-2-aminetrifluoroacetate

A mixture of the crude product from the previous step (90 mg) in TFA (2mL) was stirred under microwave at 120° C. for 30 min. The mixture wasconcentrated under reduced pressure. The residue was purified byPrep-HPLC under acidic condition to give the title compound as a lightyellow solid (55 mg, 56% over 3 steps).

MS (ES+) C₁₈H₂₀ClF₃N₈O₂ requires: 358, found: 359 [M+H]+. ¹H NMR (500MHz, DMSO-d₆) δ 13.65 (s, 1H), 8.52 (s, 1H), 8.02 (d, J=5.5 Hz, 1H),7.97 (br, 3H), 7.12 (s, 1H), 6.87 (br, 2H), 4.20-4.17 (m, 2H), 3.50-3.44(m, 2H), 1.78-1.76 (m, 4H), 1.40 (s, 3H).

Example 1074-(6-(4-(Aminomethyl)-4-methylpiperidin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-3-yl)-3-chloropyridin-2-amine

tert-Butyl (1-(6-chloro-5-(3-chloro-2-(4-methoxybenzylamino)isonicotinoyl)-pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl carbamate

To a solution of Intermediate 108 (84.4 mg, 0.2 mmol) in DMF (2 mL)under N₂ was added tert-butyl (4-methylpiperidin-4-yl)-methyl carbamate(45.6 mg, 0.2 mmol) and K₂CO₃ (55.3 mg, 0.4 mmol). The resulting mixturewas stirred overnight at RT, then poured into H₂O (20 mL). The solidthat formed was removed by filtration and dried to give the titlecompound crude as a yellow solid (120 mg) which was used directlywithout further purification.

MS (ES+) C₃₀H₃₆Cl₂N₆O₄ requires: 614, found: 615 [M+H]+.

tert-Butyl(1-(3-(3-chloro-2-(4-methoxybenzylamino)pyridin-4-yl)-1H-pyrazolo-[3,4-b]pyrazin-6-yl)-4-methylpiperidin-4-yl)methylcarbamate

To a solution of the crude product from the previous step (120 mg, 0.19mmol) in EtOH (10 mL) was added hydrazine hydrate (23 mg, 0.46 mmol).The resulting mixture was refluxed under N₂ for 2 h. The solvent wasremoved to give the title compound crude as a yellow solid (100 mg)which was used directly without further purification.

MS (ES+) C₃₀H₃₇ClN₈O₃ requires: 592, found: 593 [M+H]+.

4-(6-(4-(Aminomethyl)-4-methylpiperidin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-3-yl)-3-chloropyridin-2-amine

A mixture of the product from the previous step (100 mg, 0.16 mmol) andTFA (3 mL) was stirred at 120° C. for 20 mins with microwaveirradiation, then concentrated in vacuo and purified by HPLC to give thetitle compound as a yellow solid (19.2 mg, yield 24%).

MS (ES+) C₁₇H₂₁ClN₈ requires: 372, found: 373 [M+H]+.

1H NMR (500 MHz, DMSO) δ 13.50 (s, 1H), 8.49 (s, 1H), 8.00 (d, J=5.2 Hz,1H), 7.71 (s, 3H), 7.08 (s, 1H), 6.71-6.54 (m, 2H), 4.01 (s, 2H), 2.80(d, J=5.8 Hz, 2H), 2.36 (s, 2H), 1.56 (s, 2H), 1.47 (s, 2H), 1.09 (s,3H).

Example 1084-(6-(4-Amino-4-methylpiperidin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-3-yl)-3-chloropyridin-2-amine

(3-Chloro-2-methoxypyridin-4-yl)(3-chloro-5-((R)-1-((R)-1-(4-methoxyphenyl)-ethylamino)-8-azaspiro[4.5]decan-8-yl)pyrazin-2-yl)methanone

To a solution of Intermediate 109 (84 mg, 0.26 mmol) in DMF (5 mL),under N₂, was added(R)—N—((R)-1-(4-methoxyphenyl)ethyl)-8-azaspiro[4.5]decan-1-amine (76mg, 0.26 mmol) and K₂CO₃ (72 mg, 0.52 mmol). The resulting mixture wasstirred at RT for 4 h and then poured into H₂O (20 mL). The mixture wasextracted with EtOAc (20 mL×3). The combined organic layers were washedwith brine, dried over Na₂SO₄ and concentrated to give the titlecompound crude as a yellow solid (130 mg) which was used directlywithout further purification.

MS (ES+) C₂₉H₃₃Cl₂N₅O₃ requires: 569, found: 570.3 [M+H]+.

(R)-8-(3-(3-Chloro-2-methoxypyridin-4-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-N—((R)-1-(4-methoxyphenyl)ethyl)-8-azaspiro[4.5]decan-1-amine

To a solution of the crude product from the previous step (130 mg, 0.23mmol) in EtOH (10 mL) was added hydrazine hydrate (23 mg, 0.46 mmol).The resulting mixture was refluxed under N₂ overnight. The solvent wasremoved to give the crude title compound as a yellow solid (100 mg),which was used directly without further purification.

MS (ES+) C₂₉H₃₄ClN₇O₂ requires: 547, found: 548.3 [M+H]+.

(R)-4-(6-(1-Amino-8-azaspiro[4.5]decan-8-yl)-1H-pyrazolo[3,4-b]pyrazin-3-yl)-3-chloropyridin-2-oltrifluoroacetate

A mixture of the crude product from the previous step (100 mg) inHBr/AcOH (5 mL) was stirred at 50° C. overnight. The solvent was removedand the residue was dissolved in TFA (2 mL). The mixture was stirredunder microwave at 120° C. for 30 min. The mixture was concentratedunder reduced pressure. and the residue was purified by Prep-HPLC underacidic condition to give the title compound as a light yellow solid (11mg, 8% over 3 steps).

MS (ES+) C₂₁H₂₃ClF₃N₇O₃ requires: 399, found: 400.2 [M+H]+. 1H NMR (500MHz, DMSO-d₆) δ 13.60 (s, 1H), 12.24 (br, 1H), 8.53 (s, 1H), 7.75 (br,3H), 7.49 (s, 1H), 6.69 (d, J=8.0 Hz, 1H), 4.42-4.32 (m, 2H), 3.23-3.14(m, 3H), 2.05-1.42 (m, 10H).

Example 109(S)-4-(6-(4-Amino-2-oxa-8-azaspiro[4.5]decan-8-yl)-1H-pyrazolo[3,4-b]pyrazin-3-yl)-3-chloropyridin-2-ol

(3-Chloro-2-methoxypyridin-4-yl)(3-chloro-5-((S)-4-((R)-1-(4-methoxy-phenyl)ethylamino)-2-oxa-8-azaspiro[4.5]decan-8-yl)pyrazin-2-yl)methanone

A mixture of Intermediate 109 (61 mg, 0.2 mmol), Intermediate 103 (58mg, 0.2 mmol), K₂CO₃ (55 mg, 0.4 mmol) and DMF (5 mL) was stirred at RTfor 1 h. The reaction was quenched with H₂O (10 mL). The solid thatformed was removed by filtration and dried in vacuo to give the titlecompound as a light solid (100 mg, yield 88%).

MS (ES+) C₂₈H₃₁Cl₂N₅O₄ requires: 571, found: 572 [M+H]+.

(S)-8-(3-(3-chloro-2-methoxypyridin-4-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-N—((R)-1-(4-methoxyphenyl)ethyl)-2-oxa-8-azaspiro[4.5]decan-4-amine

A mixture of the product from the previous step (100 mg, 0.18 mmol),N₂H₄.H₂O (0.5 mL) and EtOH (5 mL) was stirred at 80° C. for 2 h,concentrated in vacuo to give the titled compound as a gray solid (80mg, yield 81%).

MS (ES+) C₂₈H₃₂ClN₇O₃ requires: 549, found: 550 [M+H]+.

(S)-4-(6-(4-Amino-2-oxa-8-azaspiro[4.5]decan-8-yl)-1H-pyrazolo[3,4-b]pyrazine-3-yl)-3-chloropyridin-2-ol

A mixture of the product from the previous step (80 mg, 0.15 mmol) andHBr in CH₃COOH (5 mL) was stirred at 80° C. for 1 h, concentrated invacuo and purified by HPC to give the title compound as a yellow solid(20 mg, yield 42%). MS (ES+) C₁₈H₂O ClN₇O₂ requires: 401, found:402[M+H]+.

1H NMR (500 MHz, MeOD-d4) δ 8.42 (s, 1H), 7.52 (d, J=8.5 Hz, 1H), 6.80(d, J=8.5 Hz, 1H), 4.49-4.42 (m, 2H), 4.39 (m, 1H), 4.04 (d, 1H), 3.96(d, 1H), 3.86 (d, 1H), 3.61 (t, 1H), 3.59 (m, 1H), 1.86-1.80 (m, 4H).

Example 1104-(6-(4-Amino-4-(hydroxymethyl)piperidin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-3-yl)-3-chloropyridin-2-ol

Benzyl1-(6-chloro-5-(3-chloro-2-methoxyisonicotinoyl)pyrazin-2-yl)-4-(hydroxymethyl)piperidin-4-ylcarbamate

A mixture of Intermediate 109 (61 mg, 0.2 mmol), benzyl4-(hydroxymethyl)piperidin-4-yl carbamate (52 mg, 0.2 mmol), K₂CO₃ (55mg, 0.4 mmol) and DMF (5 mL) was stirred at RT for 1 h. The reaction wasquenched with H₂O (10 mL). The solid that formed was removed byfiltration and dried in vacuo to give the title compound as a lightsolid (100 mg, yield 91%).

MS (ES+) C₂₅H₂₅Cl₂N₅O₅ requires: 545, found: 546 [M+H]+.

Benzyl1-(3-(3-chloro-2-methoxypyridin-4-yl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)-4-(hydroxymethyl)piperidin-4-ylcarbamate

A mixture of the product from the previous step (100 mg, 0.18 mmol),N₂H₄.H₂O (0.5 mL) and EtOH (5 mL) was stirred at 80° C. for 2 h, thenconcentrated in vacuo to give the titled compound as a gray solid (80mg, yield 83%).

MS (ES+) C₂₅H₂₆ClN₇O₄ requires: 523, found: 524 [M+H]+.

(4-Amino-1-(3-(3-chloro-2-methoxypyridin-4-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)piperidin-4-yl)methanol

A mixture of the product from the previous step (80 mg, 0.15 mmol) andTFA (5 mL) was stirred at 120° C. for 20 mins with microwaveirradiation, then concentrated in vacuo to give the titled compound as ayellow oil (50 mg, yield 86%).

MS (ES+) C₁₇H₂O ClN₇O₂ requires: 389, found: 390[M+H]+.

4-(6-(4-Amino-4-(hydroxymethyl)piperidin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-3-yl)-3-chloropyridin-2-ol

A mixture of the product from the previous step (50 mg, 0.12 mmol) andHBr in CH₃COOH (2 mL) was stirred at 80° C. for 1 h, then concentratedin vacuo and purified by HPLC to give the titled compound as a yellowsolid (25 mg, yield 56%).

MS (ES+) C₁₆H₁₈ClN₇O₂ requires: 375, found: 376[M+H]+. 1H NMR (500 MHz,MeOD-d4) δ 8.44 (s, 1H), 7.52 (d, J=8.5 Hz, 1H), 6.81 (d, J=8.5 Hz, 1H),4.24-4.20 (m, 2H), 3.81 (s, 2H), 3.68-3.62 (m, 2H), 2.71 (s, 1H), 2.09(m, 2H), 1.92 (m, 2H).

Example 111(R)-8-(3-(3-Chloro-2-(methylamino)pyridin-4-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-8-azaspiro[4.5]decan-1-amine

(3-Chloro-2-(methylamino)pyridin-4-yl)(3-chloro-5-((1R)-1-(1-(4-methoxy-phenyl)ethylamino)-8-azaspiro[4.5]decan-8-yl)pyrazin-2-yl)methanone

To a solution of(3-chloro-2-(methylamino)pyridin-4-yl)(3,5-dichloropyrazin-2-yl)methanone(63.2 mg, 0.2 mmol) in DMF (2 mL) under nitrogen was added(1R)—N-(1-(4-methoxyphenyl)ethyl)-8-azaspiro[4.5]decan-1-amine (57.6 mg,0.2 mmol) and K₂CO₃ (55.3 mg, 0.4 mmol). The resulting mixture wasstirred overnight at r.t. for 1 h and then poured into water (20 mL).The solid was collected and dried to give the title compound as a yellowsolid (120 mg) which was used directly without further purification.

MS (ES+) C₂₉H₃₄Cl₂N₆O₂ requires: 568, found: 569 [M+H]+.

(1R)-8-(3-(3-Chloro-2-(methylamino)pyridin-4-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-N-(1-(4-methoxyphenyl)ethyl)-8-azaspiro[4.5]decan-1-amine

To a solution of the crude product from the previous step (120 mg, 0.21mmol) in EtOH (10 mL) was added hydrazine hydrate (23 mg, 0.46 mmol).The resulting mixture was refluxed under nitrogen for 2 h. The solventwas removed to give the crude title compound as a yellow solid (100 mg)which was used directly without further purification.

MS (ES+) C₂₉H₃₅ClN₈O requires: 546, found: 547[M+H]+.

(R)-8-(3-(3-Chloro-2-(methylamino)pyridin-4-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-8-azaspiro[4.5]decan-1-amine

A solution of the product from the previous step (100 mg, 0.21 mmol) inTFA (5 mL) was stirred at RT for 2 h, then concentrated under reducedpressure. The residue was purified by Prep-HPLC to give the titlecompound as a yellow solid (33.3 mg, yield 65%).

MS (ES+) C₂₀H₂₅ClN₈ requires: 412, found: 413 [M+H]+. 1H NMR (500 MHz,DMSO) δ 13.50 (s, 1H), 8.50 (s, 1H), 8.08 (d, J=5.2 Hz, 1H), 7.78 (s,3H), 7.00 (d, J=5.1 Hz, 1H), 6.82 (s, 1H), 4.38-4.31 (m, 2H), 3.17 (dd,J=23.7, 9.1 Hz, 3H), 2.93 (s, 3H), 2.06 (d, J=7.0 Hz, 1H), 1.85-1.40 (m,9H).

Example 1124-(6-(4-Amino-4-methylpiperidin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-3-yl)-3-chloro-N-methylpyridin-2-amine

tert-Butyl 1-(6-chloro-5-(3-chloro-2-(methylamino)isonicotinoyl)pyrazin-2-yl)-4-methylpiperidin-4-yl carbamate

To a solution of(3-chloro-2-(methylamino)pyridin-4-yl)(3,5-dichloropyrazin-2-yl)methanone(63.2 mg, 0.2 mmol) in DMF (2 mL) under N₂ was added tert-butyl4-methylpiperidin-4-yl carbamate (42.8 mg, 0.2 mmol) and K₂CO₃ (55.3 mg,0.4 mmol). The resulting mixture was stirred overnight at RT for 1 h andthen poured into water (20 mL). The solid was collected and dried togive the title compound as a yellow solid (120 mg) which was useddirectly without further purification.

MS (ES+) C₂₂H₂₈Cl₂N₆O₃ requires: 494, found: 495 [M+H]+.

tert-Butyl1-(3-(3-chloro-2-(methylamino)pyridin-4-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-4-methylpiperidin-4-ylcarbamate

To a solution of the crude product from the previous step (120 mg, 0.24mmol) in EtOH (10 mL) was added hydrazine hydrate (23 mg, 0.46 mmol).The resulting mixture was refluxed under nitrogen for 2 h. The solventwas removed to give the crude title compound as a yellow solid (100 mg)which was used directly without further purification.

MS (ES+) C₂₂H₂₉ClN₈O₂ requires: 472, found: 473 [M+H]+.

4-(6-(4-Amino-4-methylpiperidin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-3-yl)-3-chloro-N-methylpyridin-2-amine

A solution of the product from the previous step (100 mg, 0.21 mmol) inTFA (5 mL) was stirred at RT for 2 h, then concentrated under reducedpressure. The residue was purified by Prep-HPLC to give the titlecompound as a yellow solid. (15 mg, yield 20%).

MS (ES+) C₁₇H₂₁ClN₈ requires: 372, found: 373 [M+H]+. 1H NMR (500 MHz,DMSO) δ 13.57 (s, 1H), 8.51 (s, 1H), 8.08 (d, J=5.2 Hz, 1H), 7.97 (s,3H), 7.00 (d, J=5.2 Hz, 1H), 6.87 (s, 1H), 4.18 (d, J=14.0 Hz, 2H),3.49-3.37 (m, 2H), 2.93 (s, 3H), 1.77 (d, J=4.6 Hz, 4H), 1.40 (s, 3H).

Example 113 a/b4-(6-(4-(1-Aminoethyl)-4-methylpiperidin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-3-yl)-3-chloropyridin-2-amine

(R)—N-(1-(1-(6-chloro-5-(3-chloro-2-(4-methoxybenzylamino)isonicotinoyl)-pyrazin-2-yl)-4-methylpiperidin-4-yl)ethyl)-2-methylpropane-2-sulfinamide

To a mixture of(R)-2-methyl-N-(1-(4-methylpiperidin-4-yl)ethyl)propane-2-sulfinamide(isomer 1: 300 mg, crude) in DMF (5 mL) was added(3-chloro-2-(4-methoxybenzylamino)pyridin-4-yl)(3,5-dichloropyrazin-2-yl)methanone(200 mg) and K₂CO₃ (300 mg). The mixture was stirred at RT for 2 hours.Water (20 mL) was added and the mixture was extracted with EtOAc (20mL×3). The combined organic phases were washed with brine (20 mL) andconcentrated to obtain the title compound as brown oil (500 mg, crude).

MS (ES+) C₃₀H₃₈Cl₂N₆O₃S requires: 632, found: 633 [M+H]+.

The same method for isomer 2.

(R)—N-(1-(1-(3-(3-chloro-2-(4-methoxybenzylamino)pyridin-4-yl)-1H-pyrazolo[3,4-b]-pyrazin-6-yl)-4-methylpiperidin-4-yl)ethyl)-2-methylpropane-2-sulfinamide

To a solution of the product from the previous step (isomer 1: 500 mg,crude) in EtOH (10 mL) was added NH₂NH₂ (98%, 0.5 mL). The mixture wasstirred at 80° C. for 2 hours and then concentrated to obtain the titlecompound as a brown solid (600 mg, crude).

MS (ES+) C₃₀H₃₉ClN₈O₂S requires: 611, found: 612 [M+H]+.

The same method was used for isomer 2.

4-(6-(4-(1-Aminoethyl)-4-methylpiperidin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-3-yl)-3-chloropyridin-2-amine

A solution of the product from the previous step (isomer 1: 600 mg,crude) in TFA (2 mL) was stirred under microwave irradiation at 120° C.for 20 min. The mixture was concentrated and dissolved in DMF purifiedby Pre-HPLC to obtain the title compound as a white solid (isomer 1: 40mg; isomer 2: 42 mg).

Isomer 1 (Example 114a): MS (ES+) C₁₈H₂₃ClN₈ requires: 386, found: 387[M+H]+; 1H NMR (500 MHz, DMSO) δ 8.43 (s, 1H), 7.98 (d, J=5.0 Hz, 1H),6.99 (d, J=5.0 Hz, 1H), 6.36 (s, 2H), 4.16 (m, 2H), 3.30-3.05 (m, 3H),2.54 (m, 1H), 1.49 (m, 3H), 1.35 (m, 1H), 1.06-0.79 (m, 6H).

Isomer 2 (Example 114b): MS (ES+) C₁₈H₂₃ClN₈ requires: 386, found: 387[M+H]+; 1H NMR (500 MHz, DMSO) δ 8.43 (s, 1H), 7.98 (d, J=5.0 Hz, 1H),6.99 (d, J=5.0 Hz, 1H), 6.37 (s, 2H), 4.18 (m, 2H), 3.26 (m, 2H), 2.54(m, 1H), 1.47 (m, 3H), 1.34 (m, 1H), 1.06-0.73 (m, 6H).

Example 1141-(3-(2-Amino-3-chloropyridin-4-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-4-(aminomethyl)piperidin-4-ol

tert-Butyl(1-(6-chloro-5-(3-chloro-2-(4-methoxybenzylamino)isonicotinoyl)-pyrazin-2-yl)-4-hydroxypiperidin-4-yl)methylcarbamate

To a solution of Intermediate 108 (84.4 mg, 0.2 mmol) in DMF (2 mL)under N₂ was added tert-butyl (4-hydroxypiperidin-4-yl)methyl carbamate(46 mg, 0.2 mmol) and K₂CO₃ (55.3 mg, 0.4 mmol). The result mixture wasstirred overnight at RT then poured into H₂O (20 mL). The solid thatformed was removed via filtration and dried to give the crude titlecompound as a yellow solid (120 mg) which was used directly withoutfurther purification.

MS (ES+) C₂₉H₃₄Cl₂N₆O₅ requires: 616, found: 617 [M+H]+.

tert-Butyl(1-(3-(3-chloro-2-(4-methoxybenzylamino)pyridin-4-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-4-hydroxypiperidin-4-yl)methyl carbamate

To a solution of the crude product from the previous step (120 mg, 0.19mmol) in EtOH (10 mL) was added hydrazine hydrate (23 mg, 0.46 mmol).The resulting mixture was refluxed under N₂ for 2 h. The solvent wasremoved to give the crude title compound (100 mg), which was useddirectly without further purification.

MS (ES+) C₂₉H₃₅ClN₈O₄ requires: 594, found: 595 [M+H]+.

1-(3-(2-Amino-3-chloropyridin-4-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-4-aminomethyl)piperidin-4-ol

A mixture of the product from the previous step (100 mg, 0.16 mmol) andTFA (3 mL) was stirred at 120° C. for 20 mins with microwaveirradiation, then concentrated in vacuo and purified by HPLC to give thetitled compound as a yellow solid (36 mg, yield 48%).

MS (ES+) C₁₆H₁₉ClN₈O requires: 374, found: 375 [M+H]+. 1H NMR (500 MHz,DMSO) δ 13.55 (s, 1H), 8.52 (s, 1H), 8.00 (d, J=5.2 Hz, 1H), 7.76 (s,3H), 7.10 (s, 1H), 6.74 (s, 2H), 5.23-5.15 (m, 1H), 4.20 (d, J=14.0 Hz,2H), 3.45 (d, J=9.4 Hz, 2H), 2.82 (d, J=5.9 Hz, 2H), 1.64 (s, 4H).

Example 1157-(3-(2-Amino-3-chloropyridin-4-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-7-azaspiro[3.5]nonan-1-amine

Benzyl 7-(6-chloro-5-(3-chloro-2-(4-methoxybenzylamino)isonicotinoyl)pyrazine-2-yl)-7-azaspiro[3.5]nonan-1-yl carbamate

A mixture of Intermediate 108 (150 mg, 0.35 mmol), benzyl7-azaspiro[3.5] nonan-1-yl carbamate (97 mg, 0.35 mmol), K₂CO₃ (193 mg,1.4 mmol) and DMF (5 mL) was stirred at RT for 1 h. The reaction wasquenched with H₂O (10 mL). The solid that formed was removed byfiltration and dried in vacuo to give the title compound as a lightsolid (200 mg, yield 87%).

MS (ES+) C₃₄H₃₄Cl₂N₆O₄ requires: 660, found: 661 [M+H]+.

Benzyl7-(3-(3-chloro-2-(4-methoxybenzylamino)pyridin-4-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-7-azaspiro[3.5]nonan-1-ylcarbamate

A mixture of the product from the previous step (200 mg, 0.30 mmol),N₂H₄.H₂O (1 mL) and EtOH (5 mL) was stirred at 80° C. for 2 h, thenconcentrated in vacuo to give the title compound (160 mg, yield 84%).

MS (ES+) C₃₄H₃₅ClN₈O₃ requires: 638, found: 639 [M+H]+.

7-(3-(2-amino-3-chloropyridin-4-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-7-azaspiro[3.5]nonan-1-amine

A mixture of the product from the previous step (160 mg, 0.25 mmol) andTFA (5 mL) was stirred at 120° C. for 20 mins under microwaveirradiation, then concentrated in vacuo, and purified by HPLC to givethe title compound as a yellow solid (50 mg, yield 52%).

MS (ES+) C₁₈H₂₁ClN₈ requires: 384, found: 385[M+H]+. 1H NMR (500 MHz,MeOD-d4) δ 8.44 (s, 1H), 7.99 (d, J=6 Hz, 1H), 7.44 (d, 1H), 4.59 (d,1H), 4.45 (d, 1H), 3.53 (m, 1H), 3.28-3.25 (m, 2H), 3.12 (m, 1H), 2.43(m, 1H), 2.17 (m, 2H), 1.97-1.86 (m, 4H), 1.82 (m, 1H).

Chiral HPLC gave two isomers with retention times 12.13 and 14.24 mins[Column:IC (4.6*250 mm Sum), Mobile phase: n-Hexane (0.1% DEA): EtOH(0.1% DEA)=50:50, Flowrate: 1.0 mL/min, Temp. 40° C.].

Example 116(S)-8-(3-(2-Amino-3-chloropyridin-4-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-2-oxa-8-azaspiro[4.5]decan-4-amine

(3-Chloro-2-(4-methoxybenzylamino)pyridin-4-yl)(3-chloro-5-((S)-4-((R)-1-(4-methoxyphenyl)ethylamino)-2-oxa-8-azaspiro[4.5]decan-8-yl)pyrazin-2-yl)methanone

A mixture of Intermediate 108 (84 mg, 0.2 mmol), Intermediate 103 (58mg, 0.2 mmol), K₂CO₃ (55 mg, 0.4 mmol) and DMF (5 mL) was stirred at r.tfor 1 h. The reaction was quenched with H₂O (10 mL), and the solid thatformed was removed by filtration and dried in vacuo to give the titlecompound as a light solid (100 mg, yield 74%).

MS (ES+) C₃₅H₃₈Cl₂N₆O₄ requires: 676, found: 677 [M+H]+.

(S)-8-(3-(3-Chloro-2-(4-methoxybenzylamino)pyridin-4-yl)-1H-pyrazolo[3,4-b]-pyrazin-6-yl)-N—((R)-1-(4-methoxyphenyl)ethyl)-2-oxa-8-azaspiro[4.5]decan-4-amine

A mixture of (3-chloro-2-(4-methoxybenzylamino)pyridin-4-yl)(3-chloro-5-((5)-4-((R)-1-(4-methoxyphenyl)ethylamino)-2-oxa-8-azaspiro[4.5]decan-8-yl)pyrazin-2-yl)methanone(100 mg, 0.15 mmol), N₂H₄.H₂O (0.5 mL) and EtOH (5 mL) was stirred at80° C. for 2 h, then concentrated in vacuo to give the titled compoundas a gray solid (80 mg, yield 81%). MS (ES+) C₃₅H₃₉ClN₈O₃ requires: 654,found: 655 [M+H]+.

(S)-8-(3-(2-Amino-3-chloropyridin-4-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-2-oxa-8-azaspiro[4.5]decan-4-amine

A mixture of(5)-8-(3-(3-chloro-2-(4-methoxybenzyl-amino)pyridin-4-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-N—((R)-1-(4-methoxyphenyl)ethyl)-2-oxa-8-azaspiro[4.5]decan-4-amine(80 mg, 0.12 mmol) and TFA (5 mL) was stirred at 120° C. for 20 minsunder microwave irradiation, concentrated in vacuo, purified by HPLC togive the titled compound as a yellow solid (20 mg, yield 42%).

MS (ES+) C₁₈H₂₁ClN₈O requires: 400, found: 401[M+H]+. 1H NMR (500 MHz,MeOD-d4) δ 8.46 (s, 1H), 7.99 (d, J=9 Hz, 1H), 7.47 (d, J=9 Hz, 1H),4.24-4.20 (m, 2H), 4.04 (m, 1H), 3.95 (t, 1H), 3.87 (t, 1H), 3.84 (t,1H), 3.62 (t, 1H), 3.33 (m, 1H), 3.20 (m, 1H), 1.88-1.80 (m, 4H).

Example 1174-(6-(4-Amino-4-methylpiperidin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-3-yl)-3-chloropyridin-2-ol

tert-Butyl 1-(6-chloro-5-(3-chloro-2-methoxyisonicotinoyl)pyrazin-2-yl)-4-methylpiperidin-4-yl carbamate

To a solution of Intermediate 109 (63.7 mg, 0.2 mmol) in DMF (2 mL)under N₂ was added tert-butyl 4-methylpiperidin-4-yl carbamate (42.8 mg,0.2 mmol) and K₂CO₃ (55.3 mg, 0.4 mmol). The resulting mixture wasstirred overnight at RT and poured into H₂O (20 mL). The solid thatformed was removed by filtration and dried to give the crude titlecompound as a yellow solid (120 mg) which was used directly withoutfurther purification. MS (ES+) C₂₂H₂₇Cl₂N₅O₄ requires: 495, found: 496[M+1-1]+.

tert-Butyl1-(3-(3-chloro-2-methoxypyridin-4-yl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)-4-methylpiperidin-4-ylcarbamate

To a solution of the crude product from the previous step (120 mg, 0.23mmol) in EtOH (10 mL) was added hydrazine hydrate (23 mg, 0.46 mmol).The resulting mixture was refluxed under N₂ for 2 h. The solvent wasremoved to give the crude title compound as a yellow solid (100 mg)which was used directly without further purification. MS (ES+)C₂₂H₂₈ClN₇O₃ requires: 473, found: 474[M+H]+.

4-(6-(4-Amino-4-methylpiperidin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-3-yl)-3-chloropyridin-2-ol

A solution of the product from the previous step (100 mg, 0.21 mmol) inHBr/CH₃COOH (45%, 10 mL) was stirred at 40° C. for 5 h, thenconcentrated under reduced pressure. The residue was purified byPrep-HPLC to give the titled compound as a yellow solid (43.2 mg, yield60%).

MS (ES+) C₁₆H₁₈ClN₇O requires: 359, found: 360 [M+H]+. 1H NMR (500 MHz,DMSO) δ 13.66 (s, 1H), 12.23 (s, 1H), 8.53 (s, 1H), 7.95 (s, 3H), 6.69(d, J=6.7 Hz, 1H), 4.19 (d, J=13.9 Hz, 2H), 3.46 (d, J=6.9 Hz, 2H), 1.77(d, J=4.9 Hz, 4H), 1.40 (s, 3H).

Example 1181-(3-(2-Amino-3-chloropyridin-4-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-4(aminomethyl)piperidin-4-ol

tert-Butyl (1-(6-chloro-5-(3-chloro-2-methoxyisonicotinoyl)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl carbamate

To a solution of Intermediate 109 (63.7 mg, 0.2 mmol) in DMF (2 mL)under N₂ was added tert-butyl (4-methylpiperidin-4-yl)methyl carbamate(45.6 mg, 0.2 mmol) and K₂CO₃ (55.3 mg, 0.4 mmol). The resulting mixturewas stirred overnight at RT and then poured into H₂O (20 mL). The solidthat formed was removed by filtration and dried to give the titlecompound crude as a yellow solid (120 mg) which was used directlywithout further purification.

MS (ES+) C₂₃H₂₉Cl₂N₅O₄ requires: 509, found: 510 [M+H]+.

tert-Butyl (1-(3-(3-chloro-2-methoxypyridin-4-yl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)-4-methylpiperidin-4-yl)methyl carbamate

To a solution of the crude product from the previous step (120 mg, 0.23mmol) in EtOH (10 mL) was added hydrazine hydrate (23 mg, 0.46 mmol).The resulting mixture was refluxed under N₂ for 2 h. The solvent wasremoved to give the title compound crude as a yellow solid (100 mg),which was used directly without further purification.

MS (ES+) C₂₃H₃₀ClN₇O₃ requires: 487, found: 488[M+H]+.

4-(6-(4-(Aminomethyl)-4-methylpiperidin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-3-yl)-3-chloropyridin-2-ol

A solution of the product from the previous step (100 mg, 0.20 mmol) inHBr/CH₃COOH (45%, 10 mL) was stirred at 40° C. for 5 h, thenconcentrated under reduced pressure. The residue was purified byPrep-HPLC to give the title compound as a yellow solid (42.3 mg, yield56%).

MS (ES+) C₁₇H₂₀ClN₇O requires: 373, found: 374 [M+H]+. 1H NMR (500 MHz,DMSO) δ 13.57 (s, 1H), 12.22 (s, 1H), 8.51 (s, 1H), 7.71 (s, 3H), 7.49(d, J=6.8 Hz, 1H), 6.70 (d, J=6.7 Hz, 1H), 4.03 (d, J=14.1 Hz, 2H), 3.51(t, J=10.1 Hz, 2H), 2.80 (d, J=5.8 Hz, 2H), 1.56 (t, J=9.8 Hz, 2H), 1.45(d, J=14.3 Hz, 2H), 1.09 (s, 3H).

Example 119(4-Amino-1-(3-(2-amino-3-chloropyridin-4-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-piperidin-4-yl)methanol

Benzyl 1-(6-chloro-5-(3-chloro-2-(4-methoxybenzylamino)isonicotinoyl)pyrazine-2-yl)-4-(hydroxymethyl)piperidin-4-yl carbamate

A mixture of Intermediate 108 (84 mg, 0.2 mmol), benzyl4-(hydroxymethyl)piperidin-4-yl carbamate (52 mg, 0.2 mmol), K₂CO₃ (55mg, 0.4 mmol) and DMF (5 mL) was stirred at rt for 1 h. The reaction wasquenched with H₂O (10 mL). The solid that formed was removed byfiltration and dried in vacuo to give the title compound as a lightsolid (100 mg, yield 77%).

MS (ES+) C₃₂H₃₂Cl₂N₆O₅ requires: 650, found: 651 [M+H]+.

Benzyl1-(3-(3-chloro-2-(4-methoxybenzylamino)pyridin-4-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-4-(hydroxymethyl)piperidin-4-ylcarbamate

A mixture of the product from the previous step (100 mg, 0.15 mmol),N₂H₄.H₂O (0.5 mL) and EtOH (5 mL) was stirred at 80° C. for 2 h. Themixture was concentrated in vacuo to give the title compound as a graysolid (90 mg, yield 96%).

MS (ES+) C₃₂H₃₃ClN₈O₄ requires: 628, found: 629 [M+H]+.

(4-Amino-1-(3-(2-amino-3-chloropyridin-4-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-piperidin-4-yl)methanol

A mixture of the product from the previous step and TFA (5 mL) wasstirred at 120° C. for 20 min with microwave irradiation, concentratedin vacuo and purified by HPLC to give the titled compound as a yellowsolid (30 mg, yield 58%).

MS (ES+) C₁₆H₁₉ClN₈O requires: 374, found: 375 [M+H]+. 1H NMR (500 MHz,MeOD-d4) δ 8.48 (s, 1H), 7.99 (d, J=6 Hz, 1H), 7.46 (d, J=6 Hz, 1H),4.24 (dd, J=14.5 Hz, 1H), 3.81 (s, 2H), 3.69 (dd, J=14.5 Hz, 2H), 2.09(d, J=18 Hz, 1H), 1.91 (d, J=18 Hz, 2H).

Example 1204-(6-(4-(Aminomethyl)-4-hydroxypiperidin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-3-yl)-3-chloropyridin-2-ol

tert-Butyl (1-(6-chloro-5-(3-chloro-2-methoxyisonicotinoyl)pyrazin-2-yl)-4-hydroxypiperidin-4-yl)methyl carbamate

To a solution of Intermediate 109 (63.7 mg, 0.2 mmol) in DMF (2 mL)under N₂ was added tert-butyl (4-hydroxypiperidin-4-yl)methyl carbamate(46 mg, 0.2 mmol) and K₂CO₃ (55.3 mg, 0.4 mmol). The resulting mixturewas stirred overnight at RT and poured into H₂O (20 mL). The solid thatformed was removed by filtration and dried to give the crude titlecompound as a yellow solid (120 mg) which was used directly withoutfurther purification.

MS (ES+) C₂₂H₂₇Cl₂N₅O₅ requires: 511, found: 512 [M+H]+.

tert-Butyl(1-(3-(3-chloro-2-methoxypyridin-4-yl)-1H-pyrazolo[3,4-b]pyrazine-6-yl)-4-hydroxypiperidin-4-yl)methylcarbamate

To a solution of the crude product from the previous step (120 mg, 0.19mmol) in EtOH (10 mL) was added hydrazine hydrate (23 mg, 0.46 mmol).The result mixture was refluxed under N₂ for 2 h. The solvent wasremoved to give the crude title compound as a yellow solid (100 mg)which was used directly without further purification.

MS (ES+) C₂₂H₂₈ClN₇O₄ requires: 489, found: 490[M+H]+.

4-(6-(4-(Aminomethyl)-4-hydroxypiperidin-1-yl)-1H-pyrazolo[3,4-b]pyrazine-3-yl)-3-chloropyridin-2-ol

A solution of the product from the previous step (100 mg, 0.21 mmol) inHBr/CH₃COOH (45%, 10 mL) was stirred at 40° C. for 5 h, thenconcentrated under reduced pressure. The residue was purified byPrep-HPLC to give the title compound as a yellow solid (11 mg, yield15%).

MS (ES+) C₁₆H₁₈ClN₇O₂ requires: 375, found: 376 [M+H]+. 1H NMR (500 MHz,MeOD) δ 8.41 (s, 1H), 7.51 (d, J=6.7 Hz, 1H), 6.81 (d, J=6.7 Hz, 1H),4.37 (d, J=13.6 Hz, 2H), 3.62-3.49 (m, 2H), 2.96 (s, 2H), 1.90-1.67 (m,4H).

Example 121(4-Amino-1-(3-(2-chloro-6-fluorophenyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-piperidin-4-yl)methanol

(3-Chloro-5-(4-(hydroxymethyl)-4-(4-methoxybenzylamino)piperidin-1-yl)pyrazin-2-yl)(2-chloro-6-fluorophenyl)methanone

To a solution of(2-chloro-6-fluorophenyl)(3,5-dichloropyrazin-2-yl)methanone (73 mg,0.24 mmol) in DMF (5 mL) under Na was added (4-(4-methoxybenzylamino)piperidin-4-yl)methanol dihydrochloride (78 mg, 0.24 mmol)and K₂CO₃ (136 mg, 0.96 mmol). The resulting mixture was stirred at RTfor 4 h and then poured into H₂O (20 mL). The mixture was extracted withEtOAc (20 mL×3). The combined organic layers were washed with brine,dried over Na₂SO₄ and concentrated to give the title compound crude as ayellow solid (103 mg), which was used directly without furtherpurification.

MS (ES+) C₂₅H₂₅Cl₂FN₄O₃ requires: 518, found: 519 [M+H]+.

(1-(3-(2-Chloro-6-fluorophenyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-4-(4-methoxy-benzylamino)piperidin-4-yl)methanol

To a solution of the crude product from the previous step (103 mg, 0.2mmol) in EtOH (10 mL) was added hydrazine hydrate (20 mg, 0.4 mmol). Theresulting mixture was refluxed under N₂ for 3 days. The solvent wasremoved to give the title compound crude as a yellow solid (90 mg),which was used directly without further purification.

MS (ES+) C₂₅H₂₆ClFN₆O₂ requires: 496, found: 497.2 [M+H]+.

(4-Amino-1-(3-(2-chloro-6-fluorophenyl)-1H-pyrazolo[3,4-13]pyrazin-6-yl)-piperidin-4-yl)methanoltrifluoroacetate

A mixture of the crude product from the previous step (90 mg) in TFA (2mL) was stirred under microwave at 120° C. for 30 min. The mixture wasconcentrated under reduced pressure. The residue was purified byPrep-HPLC under acidic conditions to give the title compound as a lightyellow solid (16 mg, 14% over 3 steps).

MS (ES+) C₁₉H₁₉ClF₄N₆O₃ requires: 376, found: 377.1 [M+H]+. ¹H NMR (500MHz, CD₃OD) δ 8.26 (s, 1H), 7.43-7.41 (m, 1H), 7.33 (d, J=8.5 Hz, 1H),7.15 (t, J=8.5 Hz, 1H), 4.12-4.09 (m, 2H), 3.69 (s, 2H), 3.55-3.50 (m,2H), 1.97-1.93 (m, 2H), 1.75-1.73 (s, 2H).

Example 1223-(2,3-Dichlorophenyl)-6-(2,8-diazaspiro[4.5]decan-8-yl)-1H-pyrazolo[3,4-b]pyrazine

(3-Chloro-5-((R)-1-((R)-1-(4-methoxyphenyl)ethylamino)-8-azaspiro[4.5]decan-8-yl)pyrazin-2-yl)(2-(4-methoxybenzylamino)-3-methylpyridin-4-yl)methanone

To a solution of(3,5-dichloropyrazin-2-yl)(2-(4-methoxybenzylamino)-3-methylpyridin-4-yl)-methanone (180 mg, 0.45 mmol) in DMF (2 mL) was added(R)—N—((R)-1-(4-methoxyphenyl)-ethyl)-8-azaspiro[4.5]decan-1-amine (161mg, 0.45 mmol) and K₂CO₃ (247 mg, 1.8 mmol). The resulting mixture wasstirred at RT for 2 h. The solvent was removed to give the crude titlecompound as a yellow solid (220 mg) which was used directly withoutfurther purification.

MS (ES+) C₃₇H₄₃ClN₆O₃ requires: 654, found: 655[M+H]+.

(R)-8-(3-(2-(4-Methoxybenzylamino)-3-methylpyridin-4-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-N—((R)-1-(4-methoxyphenyl)ethyl)-8-azaspiro[4.5]decan-1-amine

To a solution of the crude product from the previous step (220 mg, 0.33mmol) in EtOH (10 mL) was added hydrazine hydrate (23 mg, 0.46 mmol).The resulting mixture was refluxed under N₂ for 2 h. The solvent wasremoved to give the title compound crude as a yellow solid (180 mg)which was used directly without further purification.

MS (ES+) C₃₇H₄₄N₈O₂ requires: 632, found: 633 [M+H]+.

(R)-8-(3-(2-amino-3-methylpyridin-4-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-8-azaspiro[4.5]decan-1-amine

The solution of the crude product from the previous step (180 mg, 0.28mmol) in TFA (5 mL) was stirred at 120° C. with microwave irradiationunder Ar for 20 min, then concentrated under reduced pressure. Theresidue was purified by Prep-HPLC under acidic condition to give thetitle compound as a light yellow solid (80 mg, 37% over 3 steps).

MS (ES+) C₂₂H₂₇F₃N₈O₂ requires: 378, found: 379 [M+H]+. ¹H NMR (500 MHz,DMSO-d₆) δ 13.77 (s, 1H), 8.57 (s, 1H), 7.97 (d, J=6.5 Hz, 1H), 7.82 (s,5H), 7.46 (d, J=6.5 Hz, 1H), 4.36 (dd, J=8.5, 14 Hz, 1H), 3.21 (m, 4H),2.40 (s, 3H), 2.07 (t, J=8.0 Hz, 2H), 1.3 (m, 9H).

Example 1234-(6-(4-amino-4-methylpiperidin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-3-yl)-3-methylpyridin-2-amine

tert-Butyl1-(6-chloro-5-(2-(4-methoxybenzylamino)-3-methylisonicotinoyl)-pyrazin-2-yl)-4-methylpiperidin-4-ylcarbamate

To a solution of(3,5-dichloropyrazin-2-yl)(2-(4-methoxybenzylamino)-3-methylpyridin-4-yl)methanone (180 mg, 0.45 mmol) in DMF (2 mL) under N₂ wasadded tert-butyl 4-methylpiperidin-4-ylcarbamate (96 mg, 0.45 mmol) andK₂CO₃ (185 mg, 1.3 mmol). The resulting mixture was stirred at RT for 2h, and then poured into water (20 mL). The solid was collected and driedto give the title compound crude (220 mg) which was used directlywithout further purification.

MS (ES+) C₃₀H₃₇ClN₆O₄ requires: 580, found: 581 [M+H]+.

tert-Butyl 1-(3-(2-(4-methoxybenzylamino)-3-methylpyridin-4-yl)-1H-pyrazolo-[3,4-b]pyrazin-6-yl)-4-methylpiperidin-4-ylcarbamate

To a solution of the crude product from the previous step (220 mg, 0.38mmol) in EtOH (10 mL) was added hydrazine hydrate (38 mg, 0.76 mmol).The resulting mixture was refluxed under nitrogen for 2 h. The solventwas removed to give the title compound crude as a yellow solid (200 mg)which was used directly without further purification.

MS (ES+) C₃₀H₃₈N₈O₃ requires: 558, found: 559 [M+H]+.

4-(6-(4-Amino-4-methylpiperidin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-3-yl)-3-methylpyridin-2-amine

The solution of the crude product from the previous step (200 mg, 0.36mmol) in TFA (5 mL) was stirred at 120° C. with microwave irradiationunder Ar for 20 min, then concentrated under reduced pressure. Theresidue was purified by Prep-HPLC under acidic condition to give thetitle compound as a light yellow solid (83 mg, 41% over 3 steps).

MS (ES+) C₁₉H₂₃F₃N₈O₂ requires: 338, found: 339 [M+H]⁺. ¹H NMR (500 MHz,DMSO-d₆) δ 13.83 (s, 1H), 8.57 (s, 1H), 8.02 (s, 3H), 7.82-7.87 (m, 2H),7.46 (t, 1H), 4.18 (d, J=14.0 Hz, 2H), 3.47-3.52 (m, 2H), 2.40 (s, 3H),1.78 (d, J=5.1 Hz, 4H), 1.39 (d, J=7.9 Hz, 3H).

Example 1244-(6-(4-(Aminomethyl)-4-methylpiperidin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-3-yl)-3-methylpyridin-2-amine

tert-Butyl(1-(6-chloro-5-(2-(4-methoxybenzylamino)-3-methylisonicotinoyl)-pyrazin-2-yl)-4-methylpiperidin-4-yl)methylcarbamate

To a solution of(3,5-dichloropyrazin-2-yl)(2-(4-methoxybenzylamino)-3-methylpyridin-4-yl)methanone(180 mg, 0.45 mmol) in DMF (2 mL), under nitrogen was added tert-butyl(4-methylpiperidin-4-yl)methylcarbamate (102 mg, 0.45 mmol) and K₂CO₃(185 mg, 1.3 mmol). The resulting mixture was stirred at RT for 2 h, andthen poured into water (20 mL). The solid was collected and dried togive the title compound crude (220 mg) which was used directly withoutfurther purification.

MS (ES+) C₃₁H₃₉ClN₆O₄ requires: 594, found: 595 [M+H]+.

tert-Butyl(1-(3-(2-(4-methoxybenzylamino)-3-methylpyridin-4-yl)-1H-pyrazolo-[3,4-b]pyrazin-6-yl)-4-methylpiperidin-4-yl)methylcarbamate

To a solution of the crude product from the previous step (220 mg, 0.37mmol) in EtOH (10 mL) was added hydrazine hydrate (38 mg, 0.76 mmol).The resulting mixture was refluxed under nitrogen for 2 h. The solventwas removed to give the title compound crude as a yellow solid (200 mg)which was used directly without further purification.

MS (ES+) C₃₁H₄₀N₈O₃ requires: 572, found: 573 [M+H]+.

4-(6-(4-(Aminomethyl)-4-methylpiperidin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-3-yl)-3-methylpyridin-2-amine

A solution of the crude product from the previous step (200 mg, 0.35mmol) in TFA (5 mL) was stirred at 120° C. with microwave irradiationunder Ar for 20 min, then concentrated under reduced pressure. Theresidue was purified by Prep-HPLC under acidic condition to give thetitle compound as a light yellow solid (85 mg, 41% over 3 steps).

MS (ES+) C₂₀H₂₅F₃N₈O₂ requires: 352, found: 353 [M+H]⁺. ¹H NMR (500 MHz,DMSO-d₆) δ 13.76 (s, 1H), 8.55 (s, 1H), 7.96 (d, J=8.5 Hz, 1H),7.75-7.77 (d, J=10.0 Hz, 5H), 7.46-7.47 (d, J=7.0 Hz, 1H), 4.02 (d,J=14.1 Hz, 2H), 3.51-3.55 (m, 2H), 2.81 (d, J=5.5 Hz, 2H), 2.40 (s, 3H),1.54 (dd, J=30.2, 20.9 Hz, 4H), 1.08 (s, 3H).

Example 125(R)-8-(3-(2-amino-5-chloropyridin-4-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-8-azaspiro[4.5]decan-1-amine

(5-Chloro-2-(4-methoxybenzylamino)pyridin-4-yl)(3-chloro-5-((R)-1-((R)-1-(4-methoxyphenyl)ethylamino)-8-azaspiro[4.5]decan-8-yl)pyrazin-2-yl)methanone

To a solution of Intermediate 111 (78 mg, 0.18 mmol) in DMF (5 mL),under N₂, was added(R)—N—((R)-1-(4-methoxyphenyl)ethyl)-8-azaspiro[4.5]decan-1-amine (53mg, 0.18 mmol) and K₂CO₃ (50 mg, 0.36 mmol). The resulting mixture wasstirred at RT for 4 h and then poured into H₂O (20 mL). The mixture wasextracted with EtOAc (20 mL×3). The combined organic layers were washedwith brine, dried over Na₂SO₄ and concentrated to give the titlecompound crude as a yellow solid (108 mg) which was used directlywithout further purification.

MS (ES+) C₃₆H₄₀Cl₂N₆O₃ requires: 674, found: 675.3 [M+H]+.

(R)-8-(3-(5-Chloro-2-(4-methoxybenzylamino)pyridin-4-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-N—((R)-1-(4-methoxyphenyl)ethyl)-8-azaspiro[4.5]decan-1-amine

To a solution of the crude product from the previous step (108 mg, 0.16mmol) in EtOH (10 mL) was added hydrazine hydrate (16 mg, 0.32 mmol).The resulting mixture was refluxed under Na overnight. The solvent wasremoved to give the title compound crude as a yellow solid (100 mg),which was used directly without further purification.

MS (ES+) C₃₆H₄₁ClN₈O₂ requires: 652, found: 653.1 [M+H]+.

(R)-8-(3-(2-Amino-5-chloropyridin-4-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-8-azaspiro[4.5]decan-1-aminetrifluoroacetate

A mixture of the crude product from the previous step (100 mg) in TFA (2mL) was stirred under microwave at 120° C. for 30 min. The mixture wasconcentrated under reduced pressure. The residue was purified byPrep-HPLC under acidic condition to give the titled compound as a lightyellow solid (27.2 mg, 30% over 3 steps).

MS (ES+) C₂₁H₂₄ClF₃N₈O₂ requires: 398, found: 399.1 [M+H]+. ¹H NMR (500MHz, DMSO-d₆) δ 13.55 (s, 1H), 8.51 (s, 1H), 8.10 (s, 1H), 7.78 (br,3H), 7.09 (s, 1H), 6.68 (br, 2H), 4.40-4.32 (m, 2H), 3.23-3.14 (m, 3H),2.07-1.40 (m, 10H).

Example 126(2S,4R)-4-Amino-8-(3-(2-amino-3-chloropyridin-4-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-8-azaspiro[4.5]decan-2-ol

(R)—N-((1R,3S)-8-(6-Chloro-5-(3-chloro-2-(4-methoxybenzylamino)isonicotinoyl)pyrazin-2-yl)-3-hydroxy-8-azaspiro[4.5]decan-1-yl)-2-methylpropane-2-sulfinamide

To a solution of(R)—N-((1R,3S)-3-(tert-butyldimethylsilyloxy)-8-azaspiro[4.5]-decan-1-yl)-2-methylpropane-2-sulfinamide(40 mg, 102 μmol) and (3-chloro-2-(4-methoxybenzylamino)pyridin-4-yl)(3,5-dichloropyrazin-2-yl)methanone (43.6 mg,102 umol) in DMF (1 mL) was added K₂CO₃ (44 mg, 309 μmol). The resultingmixture was stirred at RT overnight. The mixture was then diluted withwater, and extracted with EtOAc (10 mL×3). The combined organic layerswere washed with brine (10 mL×1), dried (Na₂SO₄), filtered andconcentrated to obtain the title compound (40 mg, 59% yield) as a yellowsolid which was used directly in the next step.

MS (ES+): C₃₁H₃₈Cl₂N₆O₄S requires: 660.2, found: 661.3 [M+H]+.

N-((1R,3S)-8-(3-(3-Chloro-2-(4-methoxybenzylamino)pyridin-4-yl)-1H-pyrazolo-[3,4-b]pyrazin-6-yl)-3-hydroxy-8-azaspiro[4.5]decan-1-yl)-2-methylpropane-2-sulfinamide

To a solution of the product from the previous step (40 mg, 60.45 μmol)in EtOH (3 mL) was added hydrazine hydrate (302 μmol, 15 μL). Themixture was refluxed for 4 hours, then concentrated to obtain the crudetitle compound (32 mg, 82% yield) as a yellow solid which was useddirectly in the next step.

MS (ES+): C₃₁H₃₉ClN₈O₃S requires: 638.3, found: 639.3 [M+H]+.

(2S,4R)-4-Amino-8-(3-(2-amino-3-chloropyridin-4-yl)-1H-pyrazolo[3,4-b]-pyrazin-6-yl)-8-azaspiro[4.5]decan-2-ol

A solution of the product from the previous step (32 mg; 50.06 μmol) inTFA (1 mL) was heated at 120° C. with microwave irradiation for 20 min,cooled to RT, then concentrated. The residue was purified by Pre-HPLC toobtain the title compound (1.6 mg; 6% yield) as yellow solids.

MS (ES+): C₁₉H₂₃ClN₈O, requires: 414.2, found: 415.1 [M+H]+; 1H NMR (500MHz, MeOD) δ 8.46 (s, 1H), 7.98 (s, 1H), 7.48 (d, J=6.2 Hz, 1H),4.71-4.54 (m, 1H), 4.54-4.35 (m, 2H), 3.31-3.20 (m, 3H), 2.49-2.35 (m,1H), 2.21-2.10 (m, 1H), 2.07-1.97 (m, 1H), 1.95-1.85 (m, 2H), 1.79 (s,2H), 1.66-1.58 (m, 1H).

Example 127(1R)-8-(3-(3,5-dimethyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-8-azaspiro[4.5]decan-1-amine

6-Chloro-3-iodo-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyrazine

A solution of 6-chloro-3-iodo-1H-pyrazolo[3,4-b]pyrazine (90 mg, 0.3mmol) in DMF (2 mL) was added Cs₂CO₃ (260 mg, 0.8 mmol) and4-methoxybenzyl chloride (75 mg, 0.5 mmol). The reaction mixture wasstirred at RT overnight. The reaction mixture was diluted with EtOAc (50mL) and washed with brine (50 ml×3). The organic layer was dried (MgSO₄)and concentrated in vacuo. The residue was purified by silica gel columnchromatography (Petroleum ether:EtOAc=2:1) to give the title compound asa white solid (70 mg, 55%).

MS (ES+) C₆H₅FIN requires: 400, found: 401 [M+H]+. 1H NMR (500 MHz,CDCl₃) δ 8.45 (s, 1H), 7.30 (d, J=9.0 Hz, 2H), 6.78 (d, J=9.0 Hz, 2H),5.50 (s, 2H), 3.71 (s, 3H).

6-Chloro-3-(3,5-dimethyl-1H-pyrazol-4-yl)-1-(4-methoxybenzyl)-1H-pyrazolo-[3,4-b]pyrazine

A solution of the product from the previous step (60 mg, 0.15 mmol) indioxane/H₂O (6/2 mL) was treated with3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(39 mg, 0.18 mmol), PdCl₂dppf (20 mg, 0.03 mmol) and KOAc (36 mg, 0.36mmol). The resulting mixture was refluxed under N₂ overnight, thenfiltered. The filtrate was concentrated under reduced pressure, and theobtained residue was purified by silica gel column chromatography(Petroleum ether:EtOAc=1:1) to give the title compound as a white solid(25 mg, 45%).

MS (ES+) C₁₈H₁₇ClN₆O requires: 368, found: 369 [M+H]+.

(1R)-8-(3-(3,5-dimethyl-1H-pyrazol-4-yl)-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-N—((R)-1-(4-methoxyphenyl)ethyl)-8-azaspiro[4.5]decan-1-amine

To a solution of the product from the previous step (25 mg, 0.07 mmol)in DMF (2 mL) was added(R)—N—((R)-1-(4-methoxyphenyl)ethyl)-8-azaspiro[4.5]decan-1-amine (20mg, 0.07 mmol) and K₂CO₃ (28 mg, 0.2 mmol). The resulting mixture wasstirred at RT overnight, then filtered. The solvent was removed to givethe crude title compound as a yellow solid (18 mg) which was useddirectly without further purification.

MS (ES+) C₃₆H₄₄N₈O₂ requires: 620, found: 621 [M+H]+.

(1R)-8-(3-(3,5-dimethyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-8-azaspiro[4.5]decan-1-amine

A mixture of the crude product from the previous step (18 mg, 0.03 mmol)and TFA (2 mL) was stirred at 120° C. with microwave irradiation underAr for 20 min, then concentrated under reduced pressure. The residue waspurified by Prep-HPLC under acidic conditions to give the title compoundas a white solid (7 mg, 28% over 2 steps).

MS (ES+) C₁₉H₂₆N₈ requires: 366, found: 367 [M+H]+. 1H NMR (500 MHz,CD3OD-d4) δ 8.36 (s, 1H), 4.52 (d, J=13.5 Hz, 1H), 4.45 (d, J=13 Hz,1H), 3.25-3.30 (m, 4H), 2.40 (s, 6H), 2.23-2.30 (m, 1H), 1.17-1.98 (m,10H).

Example 1284-amino-1-(3-(2-amino-3-chloropyridin-4-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-piperidine-4-carboxamide

4-Amino-1-(6-chloro-5-(3-chloro-2-(4-methoxybenzylamino)isonicotinoyl)-pyrazin-2-yl)piperidine-4-carboxamide

To a solution of(3-chloro-2-(4-methoxy-benzylamino)pyridin-4-yl)(3,5-dichloropyrazin-2-yl)methanone (30 mg, 0.07 mmol) in DMF (1.5 mL) under nitrogenwas added 4-aminopiperidine-4-carboxamide dihydrochloride (15 mg, 0.07mmol) and K₂CO₃ (48 mg, 0.35 mmol). The resulting mixture was stirred atRT for 12 h and then poured into water (20 mL). The mixture was thenextracted with EtOAc (30 mL×2). The combined organic layers were washedwith brine (20 mL), dried over anhydrous Na₂SO₄, and concentrated, andthe crude product was purified by flash chromatography (DCM:MeOH=10:1)to give the title compound as a yellow solid (13 mg).

MS (ES+) C₂₄H₂₅Cl₂N₇O₃ requires: 529, found: 530[M+H]+.

4-Amino-1-(3-(3-chloro-2-(4-methoxybenzylamino)pyridin-4-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)piperidine-4-carboxamide

To a solution of the crude product from the previous step (12 mg, 0.022mmol) in EtOH (1.7 mL) was added hydrazine hydrate (98%, 2.4 mg, 0.044mmol). The resulting mixture was refluxed under N₂ for 2 h. The solventwas removed to give the title compound crude as a yellow solid (7 mg,yield 63%) which was used directly without further purification.

MS (ES+) C₂₄H₂₆ClN₉O₂ requires: 507, found: 508 [M+H]+.

4-Amino-1-(3-(2-amino-3-chloropyridin-4-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)piperidine-4-carboxamide

A mixture of the product from the previous step (6 mg, 0.012 mmol) inTFA (1.5 mL) was stirred at 120° C. for 30 min under microwaveirradiation, then concentrated in vacuo and purified by HPLC to give thetitle compound as a white solid. (2 mg, yield 43%).

MS (ES+) C₁₆H₁₈ClN₉O requires: 387, found: 388[M+H]+. 1H NMR (500 MHz,MeOD) δ 8.39 (s, 1H), 7.99 (d, J=5.1 Hz, 1H), 7.00 (d, J=5.2 Hz, 1H),4.29 (d, J=13.6 Hz, 2H), 3.63 (t, J=10.8 Hz, 2H), 2.20 (d, J=10.1 Hz,2H), 1.65 (d, J=13.5 Hz, 2H).

Example 129(R)-8-(3-(2-amino-5-methylpyridin-4-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-8-azaspiro[4.5]decan-1-amine

(3-Chloro-5-((R)-1-((R)-1-(4-methoxyphenyl)ethylamino)-8-azaspiro[4.5]decan-8-yl)pyrazin-2-yl)(2-(4-methoxybenzylamino)-5-methylpyridin-4-yl)methanone

To a solution of(3,5-dichloropyrazin-2-yl)(2-(4-methoxybenzylamino)-5-methylpyridin-4-yl)-methanone (20 mg, 0.05 mmol) in DMF (2 mL) was added(R)—N—((R)-1-(4-methoxyphenyl)-ethyl)-8-azaspiro[4.5]decan-1-amine (19mg, 0.05 mmol) and K₂CO₃ (30 mg, 0.2 mmol), and the resulting mixturewas stirred at RT for 2 h. The solvent was removed to give the titlecompound crude as a brown oil (100 mg) which was used directly withoutfurther purification.

MS (ES+) C₃₇H₄₃ClN₆O₃ requires: 654, found: 655[M+H]+.

(R)-8-(3-(2-(4-Methoxybenzylamino)-5-methylpyridin-4-yl)-1H-pyrazolo[3,4-1]-pyrazin-6-yl)-N—((R)-1-(4-methoxyphenyl)ethyl)-8-azaspiro[4.5]decan-1-amine

To a solution of the crude product from the previous step (100 mg) inEtOH (5 mL) was added hydrazine hydrate (0.5 ml). The resulting mixturewas refluxed under N₂ for 2 h. The solvent was removed to give the titlecompound as a brown oil (100 mg, crude) which was used directly withoutfurther purification.

MS (ES+) C₃₇H₄₄N₈O₂ requires: 632, found: 633 [M+H]+.

(R)-8-(3-(2-Amino-5-methylpyridin-4-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-8-azaspiro[4.5]decan-1-amine

A mixture of the crude product (100 mg) and TFA (2 mL) was stirred at120° C. with microwave irradiation under Ar for 20 min, thenconcentrated under reduced pressure. The residue was purified byPrep-HPLC to give the title compound as a white solid (1 mg).

MS (ES+) C₂₂H₂₇F₃N₈O₂ requires: 378, found: 379 [M+H]+. 1H NMR (500 MHz,MeOD) δ 8.36 (s, 1H), 7.87 (s, 1H), 7.11 (s, 1H), 4.56-4.29 (m, 2H),3.26 (t, J=7.9 Hz, 2H), 2.90 (t, J=7.3 Hz, 1H), 2.32 (s, 3H), 2.21-1.28(m, 10H).

TABLE 9 Examples 130-138. The following compounds were synthesized usingmethods as set forth previously. Name Structure Spectral data 130(1R)-8-[3-(2-amino- 3-chloropyridin-4- yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-8- azaspiro[4.5]decan- 1-amine

MS (ES+) C₂₁H₂₄ClF₃N₈O₂ requires: 398, found: 399.3 [M + H]+. ¹H NMR(400 MHz, DMSO-d6) δ 13.61 (s, 1H), 8.53 (s, 1H), 8.01 (d, J = 5.6 Hz,1H), 7.78 (br, 3H), 7.13 (d, J = 5.2 Hz, 1H), 6.88 (br, 2H), 4.40-4.32(m, 2H), 3.24- 3.14 (m, 3H), 2.05-1.40 (m, 10H). 131 (1R)-8-[3-(3-amino-2-chlorophenyl)-1H- pyrazolo[3,4-b]- pyrazin-6-yl]-8-aza-spiro[4.5]decan-1- amine

MS (ES+) C₂₂H₂₅ClF₃N₇O₂ requires: 397, found: 398.2 [M + H]+. ¹H NMR(500 MHz, DMSO-d₆) δ 13.20 (s, 1H), 8.43 (s, 1H), 7.75 (br, 3H), 7.11(t, J = 8.0 Hz, 1H), 6.88 (dd, J = 1.5, 8.0 Hz, 1H), 6.82 (dd, J = 1.5,8.0 Hz, 1H), 5.50 (br, 2H), 4.41-4.30 (m, 2H), 3.22-3.11 (m, 3H),2.05-1.39 (m, 10H). 132 3-{6-[4-(amino- methyl)-4-methyl-piperidin-1-yl]-1H- pyrazolo[3,4-b]- pyrazin-3-yl}-2- chloroaniline

MS (ES+) C₂₀H₂₃ClF₃N₇O₂ requires: 371, found: 372.2 [M + H]+. ¹H NMR(500 MHz, DMSO-d₆) δ 13.21 (s, 1H), 8.41 (s, 1H), 7.77 (br, 3H), 7.11(t, J = 8.0 Hz, 1H), 6.88 (dd, J = 1.5, 8.0 Hz, 1H), 6.82 (dd, J = 1.5,8.0 Hz, 1H), 5.11 (br, 2H), 4.02-3.99 (m, 2H), 3.51-3.47 (m, 2H),2.81-2.79 (m, 2H), 1.56-1.46 (m, 4H), 1.09 (s, 1H). 133 4-{6-[4-(amino-methyl)-4-methyl- piperidin-1-yl]-1H- pyrazolo[3,4-b]- pyrazin-3-yl}-5-chloropyridin-2- amine

MS (ES+) C₁₉H₂₂ClF₃N₈O₂ requires: 372, found: 373.1 [M + H]+. ¹H NMR(500 MHz, DMSO-d₆) δ 13.53 (s, 1H), 8.49 (s, 1H), 8.10 (s, 1H), 7.73(br, 1H), 7.09 (s, 1H), 6.72 (br, 2H), 4.04-4.01 (m, 2H), 3.54-3.49 (m,2H), 2.81- 2.79 (m, 2H), 1.59-1.44 (m, 4H), 1.09 (s, 3H). 1341-[3-(2-amino-5- chloropyridin-4-yl)- 1H-pyrazolo[3,4-b]-pyrazin-6-yl]-4- (aminomethyl)- piperidin-4-ol

MS (ES+) C₁₈H₂₀ClF₃N₈O₃ requires: 374, found: 375.1 [M + H]+. ¹H NMR(500 MHz, DMSO-d₆) δ 13.54 (s, 1H), 8.51 (s, 1H), 8.09 (s, 1H), 7.77(br, 1H), 7.07 (s, 1H), 6.65 (br, 2H), 5.20 (br, 1H), 4.21- 4.18 (m,2H), 3.49-3.43 (m, 2H), 2.82-2.81 (m, 2H), 1.64-1.60 (m, 4H). 1354-[6-(4-amino-4- ethylpiperidin-1-yl)- 1H-pyrazolo[3,4-b]-pyrazin-3-yl]-3- chloropyridin-2- amine

MS (ES+) C₁₉H₂₂ClF₃N₈O₂ requires: 372, found: 373.1 [M + H]+. 1H NMR(500 MHz, DMSO-d6) δ 13.66 (s, 1H), 8.52 (s, 1H), 8.02 (d, J = 5.5 Hz,1H), 7.94 (br, 3H), 7.13 (d, J = 5.5 Hz, 1H), 6.92 (br, 2H), 4.03-3.99(m, 2H), 3.66- 3.61 (m, 2H), 1.85-1.73 (m, 6H), 0.94 (t, J = 7.5 Hz,3H). 136 a 7-[3-(2-amino-3- chloropyridine-4-yl)- 1H-pyrazolo[3,4-b]-pyrazin-6-yl]-7-aza- spiro[3.5]nonan-1- amine, enantiomer 1

Exact mass 384 136 b 7-[3-(2-amino-3- chloropyridin-4-yl)-1H-pyrazolo-[3,4-b]- pyrazin-6-yl]-7-aza- spiro[3.5]nonan-1- amine,enantiomer 2

Exact mass 384 137 (4S)-8-[3-(2-amino- 5-chloropyridin-4-yl)-1H-pyrazolo[3,4- b]pyrazin-6-yl]-2- oxa-8-azaspiro[4.5]-decan-4-amine

MS (ES+) C₂₀H₂₂ClF₃N₈O₃ requires: 400, found: 401.1 [M + H]+. ¹H NMR(500 MHz, CD₃OD) δ 8.34 (s, 1H), 8.01 (s, 1H), 7.45 (s, 1H), 4.37-4.27(m, 2H), 4.12-4.09 (m, 1H), 3.91 (d, J = 9.0 Hz, 1H), 3.83 (d, J = 9.0Hz, 1H), 3.74 (dd, J = 10.5, 2.5 Hz), 3.50-3.49 (m, 1H), 3.32- 3.17 (m,2H), 1.79-1.67 (m, 4H). 138 4-[6-(4-amino-4- methylpiperidin-1-yl)-1H-pyrazolo[3,4- b]pyrazin-3-yl]-5- chloropyridin-2- amine

MS (ES+) C₁₈H₂₀ClF₃N₈O₂ requires: 358, found: 359.1 [M + H]+. ¹HNMR (500MHz, CD₃OD) δ 8.49 (s, 1H), 8.13 (s, 1H), 7.52 (s, 1H), 4.35-4.35 (m,2H), 3.58-3.54 (m, 2H), 1.95- 1.92 (m, 4H), 1.55 (s, 3H).

The following compounds can generally be made using the methodsdescribed above. It is expected that these compounds when made will haveactivity similar to those that have been prepared. The Examples may bemade as free bases or as TFA salts.

Name Structure 1-amino-8-(3-(2-amino-3-chloro-pyridin-4-yl)-1H-pyrazolo[3,4- b]pyrazin-6-yl)-8-azaspiro-[4.5]decan-2-ol

(4-methyl-1-(3-(2-amino-6- chloropyridin-4-yl)-1H-pyrazolo-[3,4-b]pyrazin-6-yl)piperidin-4- yl)methanamine

(4-amino-1-(3-(2-amino-6- chloropyridin-4-yl)-1H-pyrazolo[3,4-b]pyrazin-6- yl)piperidin-4-yl)-methanol trifluoroacetate

4-(aminomethyl)-1-(3-(2-amino- 6-chloropyridin-4-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)- piperidin-4-ol

1-(3-(2-amino-6-chloropyridin-4- yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-4-methylpiperidin-4-amine

(S)-8-(3-(2-amino-6-chloro- pyridin-4-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-2-oxa-8-aza- spiro[4.5]decan-4-amine

8-(3-(2-amino-6-chloropyridin-4- yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-8-azaspiro[4.5]decan-1-amine

1-amino-8-(3-(2-amino-6-chloro- pyridin-4-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-8-azaspiro- [4.5]decan-3-ol

1-amino-8-(3-(3-chloro-2- hydroxypyridin-4-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-8- azaspiro[4.5]decan-1-ol

(4-methyl-1-(3-(3-chloropyrid- azin-4-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)piperidin-4-yl)- methanamine

(4-amino-1-(3-(3-chloropyrid- azin-4-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)piperidin-4-yl)- methanol trifluoroacetate

4-(aminomethyl)-1-(3-(3- chloropyridazin-4-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)- piperidin-4-ol

1-(3-(3-(3-chloropyridazin-4-yl)- 1H-pyrazolo[3,4-b]pyrazin-6-yl)-4-methylpiperidin-4-amine

(S)-8-(3-(3-(3-chloropyridazin-4- yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-2-oxa-8-azaspiro[4.5]decan- 4-amine

8-(3-(3-(3-chloropyridazin-4-yl)- 1H-pyrazolo[3,4-b]pyrazin-6-yl)-8-azaspiro[4.5]decan-1-amine

1-amino-8-(3-(3-(3-chloropyrid- azin-4-yl)-1H-pyrazolo[3,4-b]-pyrazin-6-yl)-8-azaspiro- [4.5]decan-2-ol

4-(aminomethyl)-1-(3-(2-amino- 3,6-dichloropyridin-4-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-4- methylpiperidine

1-(3-(3-(2-amino-3,6-dichloro- pyridin-4-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-4- methylpiperidin-4-amine

(R)-8-(3-(3-(3-(2-amino-3,6- dichloropyridin-4-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-8- azaspiro[4.5]decan-1-amine

4-(aminomethyl)-1-(3-(2,3- dihydro-7-azaindol-4-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)4- methylpiperidine

1-(3-(3-(2,3-dihydro-7-azaindol- 4-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-4-methylpiperidin-4-amine

(R)-8-(3-(3-(3-(2,3-dihydro-7- azaindol-4-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-8-azaspiro- [4.5]decan-1-amine

4-(aminomethyl)-1-(3-(1,2,3,4- tetrahydro-1,8-naphthyridin-5-yl)-1H-pyrazolo[3,4-b]pyrazin-6- yl)-4-methylpiperidine

1-(3-(3-(1,2,3,4-tetrahydro-1,8- naphthyridin-5-yl)-1H-pyrazolo-[3,4-b]pyrazin-6-yl)-4- methylpiperidin-4-amine

(R)-8-(3-(3-(3-(1,2,3,4-tetra- hydro-1,8-naphthyridin-5-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)- 8-azaspiro[4.5]decan-1-amine

4-(aminomethyl)-1-(3-(2-amino- 5-methylpyridin-4-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-4- methylpiperidine

1-(3-(3-(2-amino-5-methyl- pyridin-4-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-4- methylpiperidin-4-amine

(R)-8-(3-(3-(3-(2-amino-5- methylpyridin-4-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-8- azaspiro[4.5]decan-1-amine

4-(aminomethyl)-1-(3-(3,5- dimethylpyrazol-4-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-4- methylpiperidine

1-(3-(3-(3,5-dimethylpyrazol-4- yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-4-methylpiperidin-4-amine

(R)-8-(3-(3-(3-(3,5-dimethyl- pyrazol-4-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-8-azaspiro- [4.5]decan-1-amine

4-(aminomethyl)-1-(3-(2-amino- 5-cyanopyridin-4-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-4- methylpiperidine

1-(3-(3-(2-amino-3-cyano- pyridin-4-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-4- methylpiperidin-4-amine

(R)-8-(3-(3-(3-(2-amino-3-cyano- pyridin-4-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-8-azaspiro- [4.5]decan-1-amine

4-(aminomethyl)-1-(3-(2-amino- 3-cyanopyridin-4-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)4- methylpiperidine

1-(3-(3-(2-amino-5-cyano- pyridin-4-yl)-1H-pyrazolo]3,4-b]pyrazin-6-yl)-4- methylpiperidin-4-amine

(R)-8-(3-(3-(3-(2-amino-5-cyano- pyridin-4-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-8-azaspiro- [4.5]decan-1-amine

4-(aminomethyl)-1-(3-(2-chloro- 3-(methylamino)-phenyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)4- methylpiperidine

1-(3-(3-(2-chloro-3-(methyl- amino)-phenyl)-1H-pyrazolo-[3,4-b]pyrazin-6-yl)-4- methylpiperidin-4-amine

(R)-8-(3-(3-(3-(2-chloro-3- (methylamino)-phenyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-8- azaspiro[4.5]decan-1-amine

4-(aminomethyl)-1-(3-(2-chloro- 3-(dimethylamino)-phenyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-4- methylpiperidine

1-(3-(3-(2-chloro-3-(dimethyl- amino)-phenyl)-1H-pyrazolo-[3,4-b]pyrazin-6-yl)-4- methylpiperidin-4-amine

(R)-8-(3-(3-(3-(2-chloro-3- (dimethylamino)-phenyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-8- azaspiro[4.5]decan-1-amine

1-(3-(3-(2-chloro-3-amino)- phenyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-4-(2-propyl)- piperidin-4-amine

1-(3-(3-(2-chloro-3-amino)- phenyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-4-cyano- piperidin-4-amine

1-(3-(3-(2-chloro-3-amino)- phenyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-4-(amino- methyl)-4-cyanopiperidine

Biological Activity Assay

The activity of the compounds in the Examples disclosed herein as PTPN11inhibitors is illustrated in the following assays. Other compoundslisted herein, which have not yet been made and/or tested, are predictedto have activity in these assays as well.

PTPN11 Enzymatic Assay

Recombinant full-length wild-type and E76K mutant human PTPN11 proteinswere cloned, expressed (E. coli system), and isolated via a two-steppurification of Ni affinity followed by S75 size exclusionchromatography.

Phosphatase activity of full length wild-type PTPN11(PTPN11-WT) orPTPN11-E76K mutant enzyme was measured using the fluorogenic6,8-difluoro-4-methylumbelliferyl phosphate (DiFMUP; Molecular Probes)as the substrate. Enzyme (250 pM) was incubated with or withoutincreasing concentrations of compounds in assay buffer (62.5 mM HEPES,125 mM NaCl, 1 mM EDTA, 1.25 mM TECP, 0.1% BSA) for 30 min at roomtemperature. Reaction was initiated by addition of DiFMUP (50 μM) atroom temperature in 384-well black plate with a final reaction volume of20 uL in assay buffer. After 1 hour, DiFMUP fluorescence signal wasmeasured (Ex:340/Em:460) using Envision plate reader. Dose-responsecurves were analyzed using IC₅₀ regression curve fitting (GeneDataScreener). Curves were normalized to a high controls without inhibitor,and low controls without enzyme. Results are given below in Table 1.Other compounds disclosed herein are expected to have activity similarto the results below, showing activity as PTPN11 inhibitors.

pERK AlphaScreen Protocol

KYSE-520 cells (10 k cells/well) were grown in 384-well plate in 20 uLof medium (RPMI-1640, without phenol red, containing 10% FBS) at 37° C.with 5% CO₂ overnight. DMSO (control) or increasing concentrations ofcompounds were diluted in medium, added to the 384-well plate (5uL/well, final DMSO concentration of 1%), and cells were then incubatedwith compounds for 2 hr. Phospho-ERK levels were measured usingphospho-ERK1/2 AlphaScreen SureFire (PerkinElmer, TGRESB10K) followingmanufacturer's recommendations. Dose-response curves were analyzed usingIC₅₀ regression curve fitting (GeneData Screener). Curves werenormalized to a high control without inhibitor (DMSO only), and lowcontrol (1 μM selumetinib).

TABLE 10 Biological Activity for inhibition of PTPN11-E76K mutant enzymeand pERK AlphaScreen PTPN11-E76K PERK Avg Avg IC₅₀ IC₅₀ Ex. (nM) (nm)  1109.88  2 787  3 1072.5  4 N.A.  5 N.A.  6 2  7 196 79  8 204 86  9 367482  10 333 172  11 632 1173  12 404 623  13 158 562  14 521 569  15 140103  16 169 309  17 118 82  18 141 667  19 510 534  20 326 158  21 956620  22 1747 976  23 1824 428  24 204 142  25 101 47  26 213 N.A.  27 8055  28 142 190  29 178 87  30 2509 1597  31 929 710  32 N.A. 284  33 7296  34 102 N.A.  35 304 704  36 967 320  37 623 223  38 75 40  39 158103  40 203 186  41 966 394  42 N.A. 63  43 N.A. N.A.  44 429 304  45355 1416  46 193 666  47 493 343  48 1756 586  49 143 62  50 39 34  51153 N.A.  52 313 N.A.  53 641 224  54 119 64  55 1143 712  56 552 200 57 104 53  58 338 109  59 N.A. 1040  60 918 317  61 401 221  62 N.A.310  63 N.A. 687  64A 98 34  64B 221 70  65A 235 93  65B 471 165 1011894 638 102 2154 1182 103 2603 1629 104 99 47 105 191 120 106 253 174107 162 246 108 726 6801 109 1095 10000 110 3679 7848 111 43 20 112 12858 113a 180 100 113b N.A. N.A. 114 779 2492 115 701 427 116 132 483 1171941 4779 118 1128 8284 119 422 1727 120 5372 9698 121 1083 1649 122 205N.A. 123 670 N.A. 124 377 N.A. 125 509 429 126 75 N.A. 127 N.A. N.A. 128N.A. N.A. 129 N.A. N.A. 130 83 65 131 84 35 132 119 63 133 840 533 1341532 2009 135 529 122 136a 15155 2269 136b 4318 1956 137 504 1033 138587 406 N.A. = Not Available

ERK Phosphorylation (Phospho-ERK) Target Engagement Assay

KYSE-520 cells (10 k cells/well) are plated onto 384-well plate in 20 uLof medium (RPMI-1640, without phenol red, containing 10% FBS) andincubated at 37° C., 5% CO₂ 16 h. DMSO (control) or increasingconcentrations of compounds are diluted in medium, added to the 384-wellplate (10 uL/well, final DMSO concentration of 0.5-1%), and cells arethen incubated with compounds for 2 hr. Phospho-ERK levels are measuredusing a TR-FRET based phospho-ERK1/2 HTRF kit (CisBio, 64ERKPEH)following manufacturer's recommendations, and fluorescence signal wasmeasured at 665 nm and 620 nm using Synergy Neo plate reader.Dose-response curves were analyzed using IC₅₀ regression curve fitting(GeneData Screener). Curves were normalized to a high controls withoutinhibitor, and low controls with 1 μM of selumetinib. Some compounds ofthis invention showed IC₅₀<1 μM.

TABLE 11 pERK target engagement assay Avg IC₅₀ Ex. (nM) 1 49 2 169 3 3224 73 5 N.A. 6 124

Colony Formation Assay

KYSE-520 cells (2000 cells/well) are plated in 6-well plate containing 2mL of medium (RPMI-1640, containing 10% FBS), in the presence of DMSO(control; 1% final concentration) or increasing compound concentration.After 14 days of culture at 37° C. in a humidified 5% CO₂ incubator,colonies are fixed and stained with 0.1% crystal violet and 15% ethanolsolution. Plates are imaged and colony area quantified and normalized toDMSO with ImageJ, Colony Area plugin. (Guzman, Camilo, PloS one 2014).Compounds disclosed herein are expected to have activity in inhibitingcellular proliferation and/or colony formation in the foregoing assay.

In Vivo Tumor Models

Xenografts were initiated with BT474 human breast carcinomas cell lineand maintained by serial subcutaneous transplantation in CB-17/SCID mice(Charles River). On the day of tumor implant, each test mouse received a1 mm³ BT474 fragment implanted subcutaneously in the right flank, andtumor growth was monitored as the average size approached the targetrange of 100 to 150 mm3. About three weeks post-implantation, theanimals were randomized and grouped based on tumor volume and mouse bodyweight. The animals were then dosed with Example 1 at 100 mg/kg once perday through oral gavage on a 5 days on/2 days off schedule for 4 weeks,where the first day of dosing was designated as study day 1. Tumors weremeasured in two dimensions using calipers, and volume was calculatedusing the formula: Tumor Volume (mm³)=w²×½.

Results are found in FIGS. 1 and 2. The inhibition of PTPN11 inducedsignificant suppression of tumor growth at tolerated dose in BT474(HER2+) xenograft model in mouse.

All references, patents or applications, U.S. or foreign, cited in theapplication are hereby incorporated by reference as if written herein intheir entireties. Where any inconsistencies arise, material literallydisclosed herein controls.

From the foregoing description, one skilled in the art can easilyascertain the essential characteristics of this invention, and withoutdeparting from the spirit and scope thereof, can make various changesand modifications of the invention to adapt it to various usages andconditions.

What is claimed is:
 1. A compound of structural Formula I

or a salt or tautomer thereof, wherein: a is selected from 0 and 1; b isselected from 0 and 1; R₁ is selected from halo, C₆₋₁₀aryl,C₃₋₈cycloalkyl, C₃₋₈cycloalkenyl, and a 5-9 membered heteroaryl groupcontaining 1 to 4 heteroatoms or groups independently selected from N,C(O), O, and S; said aryl or heteroaryl of R₁ is optionally substitutedwith 1 to 5 R₁₂ groups independently selected from halo, hydroxy, amino,C₁₋₄alkylamino, C₁₋₄dialkylamino, cyano, C₁₋₄alkyl, C₁₋₄alkoxy,C₁₋₄hydroxyalkyl, C₁₋₄haloalkyl, C₁₋₄aminoalkyl, C₃₋₈cycloalkyl,C₃₋₈cycloalkenyl, NR₁₅C(O)R₁₃, NR₁₅C(O)OR₁₃, NR₁₃C(O)NR₁₅R₁₆,NR₁₅S(O)R₁₃, NR₁₅S(O)₂R₁₃, C(O)NR₁₅R₁₆, S(O)NR₁₅R₁₆, S(O)₂NR₁₅R₁₆,C(O)R₁₃, C(O)OR₁₃, SR₁₃, S(O)R₁₃, and S(O)₂R₁₃; R₂, R₃, R₁₀, and R₁₁ areindependently selected from hydrogen, C₁₋₄alkyl, and C₃₋₈cycloalkyl; R₄,R₅, R₈, and R₉ are independently selected from hydrogen, cyano,C₁₋₄alkyl, C₁₋₄alkoxy, amino, hydroxy, C₃₋₈cycloalkyl, halo, andC₁₋₄alkylamino; R₆ is selected from amino, C₁₋₄aminoalkyl, andC₁₋₄alkylamino; R₇ is selected from hydrogen, cyano, amido, halo, andhydroxy, or is selected from C₁₋₄alkyl, C₁₋₄hydroxyalkyl,C₃₋₆cycloalkyl, phenyl, and 5- or 6-membered heteroaryl, any of which isoptionally substituted with one or more R₁₇ groups; or R₆ and R₇together with the carbon atom to which they are both attached form a 3-to 7-membered saturated or unsaturated ring that can contain 1 to 3heteroatoms or groups independently selected from N, C(O), O, andS(O)_(m), and that is optionally substituted with one R₁₇ group, andthat is optionally substituted with one or more R₁₈ groups; m isselected from 0, 1, and 2; any two groups selected from R₂, R₃, R₄, R₅,R₇, R₈, R₉, R₁₀ and R₁₁ can form a 5- to 6-membered ring, optionallycontaining a N, O or S heteroatom; any two groups selected from R₂, R₄,R₆, R₈ and R₁₀ can form a direct bond, or a 1 or 2 atom carbon bridge;R₁₃, R₁₅, and R₁₆ are independently selected from hydrogen, C₁₋₄alkyl,and C₃₋₈cycloakyl, wherein said alkyl or cycloalkyl is optionallysubstituted by one or more substituents selected from hydroxy, cyano andhalo; R₁₇ is selected from amino, halo, hydroxy, cyano, trifluoromethyl,trifluoromethoxy, C₁₋₄alkyl, and C₁₋₄alkoxy; and each R₁₈ isindependently selected from halo, hydroxy, and cyano.
 2. The compound asrecited in claim 1 wherein: R₁ is selected from C₆₋₁₀aryl and a 5- to9-membered heteroaryl group containing 1 to 4 heteroatoms or groupsindependently selected from N, C(O), O, and S; said aryl or heteroarylof R₁ is optionally substituted with 1 to 5 R₁₂ groups independentlyselected from halo, hydroxy, amino, C₁₋₄alkylamino, C₁₋₄dialkylamino,cyano, C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄hydroxyalkyl, C₁₋₄haloalkyl,C₁₋₄aminoalkyl, C₃₋₈cycloalkyl, C₃₋₈cycloalkenyl, NR₁₅C(O)R₁₃,NR₁₅C(O)OR₁₃, NR₁₃C(O)NR₁₅R₁₆, NR₁₅S(O)R₁₃, NR₁₅S(O)₂R₁₃, C(O)NR₁₅R₁₆,S(O)NR₁₅R₁₆, S(O)₂NR₁₅R₁₆, C(O)R₁₃, C(O)OR₁₃, SR₁₃, S(O)R₁₃, andS(O)₂R₁₃; and R₁₃, R₁₅, and R₁₆ are independently selected fromhydrogen, C₁₋₄alkyl, and C₃₋₈cycloakyl, wherein said alkyl or cycloalkylis optionally substituted by one or more substituents selected fromhydroxy, cyano and halo.
 3. The compound as recited in claim 2 wherein:R₁ is selected from C₆₋₁₀aryl and a 5- to 9-membered heteroaryl groupcontaining 1 to 4 heteroatoms or groups independently selected from N,C(O), O, and S; said aryl or heteroaryl of R₁ is optionally substitutedwith 1 to 5 R₁₂ groups independently selected from halo, hydroxy, amino,C₁₋₄alkylamino, C₁₋₄dialkylamino, C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄haloalkyl,and C₁₋₄aminoalkyl; and R₁₇ is selected from amino, halo, and hydroxy.4. The compound as recited in claim 2 wherein: R₁ is selected fromC₆₋₁₀aryl and a 5- to 9-membered heteroaryl group containing 1 to 4heteroatoms or groups independently selected from N, C(O), O, and S;said aryl or heteroaryl of R₁ is optionally substituted with 1 to 5 R₁₂groups independently selected from halo, hydroxy, amino, C₁₋₄alkylamino,C₁₋₄dialkylamino, C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄haloalkyl, andC₁₋₄aminoalkyl; R₆ is selected from amino, C₁₋₄aminoalkyl, andC₁₋₄alkylamino; and R₇ is selected from hydrogen, cyano, amido, halo,and hydroxy, or is selected from C₁₋₄alkyl, C₁₋₄hydroxyalkyl,C₃₋₆cycloalkyl, phenyl, and 5- or 6-membered heteroaryl, any of which isoptionally substituted with one or more R₁₇ groups.
 5. The compound asrecited in claim 1 wherein: R₁ is selected from C₆₋₁₀aryl and a 5- to9-membered heteroaryl group containing 1 to 4 heteroatoms or groupsindependently selected from N, C(O), O, and S; said aryl or heteroarylof R₁ is optionally substituted with 1 to 5 R₁₂ groups independentlyselected from halo, hydroxy, amino, C₁₋₄alkylamino, C₁₋₄dialkylamino,C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄haloalkyl, and C₁₋₄aminoalkyl; and R₄, R₅,R₈, and R₉ are independently selected from hydrogen, C₁₋₄alkyl,C₁₋₄alkoxy, amino, hydroxy, C₃₋₈cycloalkyl, and C₁₋₄alkylamino.
 6. Thecompound as recited in claim 5 wherein R₂, R₃, R₄, R₅, R₈, R₉, R₁₀ andR₁₁ are hydrogen.
 7. The compound as recited in claim 6 wherein R₆ andR₇ together with the carbon atom to which they are both attached form a3- to 7-membered cycloalkyl ring that is optionally substituted with oneR₁₇ group, and that is optionally substituted with one or more R₁₈groups.
 8. The compound as recited in claim 6 wherein: R₁ is selectedfrom C₆₋₁₀aryl and a 5- to 9-membered heteroaryl group containing 1 to 4heteroatoms or groups independently selected from N, C(O), O, and S;said aryl or heteroaryl of R₁ is optionally substituted with 1 to 5 R₁₂groups independently selected from halo, hydroxy, amino, C₁₋₄alkylamino,C₁₋₄dialkylamino, C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄haloalkyl, andC₁₋₄aminoalkyl; and R₁₇ is selected from amino, halo, and hydroxy. 9.The compound as recited in claim 6 wherein: R₁ is selected fromC₆₋₁₀aryl and a 5- to 9-membered heteroaryl group containing 1 to 4heteroatoms or groups independently selected from N, C(O), O, and S;said aryl or heteroaryl of R₁ is optionally substituted with 1 to 5 R₁₂groups independently selected from halo, hydroxy, amino, C₁₋₄alkylamino,C₁₋₄dialkylamino, C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄haloalkyl, andC₁₋₄aminoalkyl; R₆ is selected from amino, C₁₋₄aminoalkyl, andC₁₋₄alkylamino; and R₇ is selected from hydrogen, cyano, amido, halo,and hydroxy, or is selected from C₁₋₄alkyl, C₁₋₄hydroxyalkyl,C₃₋₆cycloalkyl, phenyl, and 5- or 6-membered heteroaryl, any of which isoptionally substituted with one or more R₁₇ groups.
 10. The compound asrecited in claim 1, wherein R₆ and R₇ together with the carbon atom towhich they are both attached forms a 3- to 7-membered saturated orunsaturated ring that can contain 1 to 3 heteroatoms or groupsindependently selected from N, C(O), O, and S(O)_(m), and that isoptionally substituted with one R₁₇ group, and that is optionallysubstituted with one or more R₁₈ groups.
 11. The compound as recited inclaim 1, wherein R₆ and R₇ together with the carbon atom to which theyare both attached forms a 3- to 7-membered cycloalkyl ring that isoptionally substituted with one R₁₇ group, and that is optionallysubstituted with one or more R₁₈ groups.
 12. The compound as recited inclaim 1, wherein R₆ and R₇ together with the carbon atom to which theyare both attached form a 3- to 6-membered heterocycloalkyl ring that isoptionally substituted with one R₁₇ group, and that is optionallysubstituted with one or more R₁₈ groups.
 13. The compound as recited inclaim 1, wherein R₆ and R₇ together with the carbon atom to which theyare both attached form a 3- to 6-membered heterocycloalkyl ring that isoptionally substituted with one R₁₇ group.
 14. The compound as recitedin claim 1, wherein R₆ is C₁₋₄aminoalkyl; and R₇ is selected fromhydroxy, or is selected from C₁₋₄alkyl, C₁₋₄hydroxyalkyl,C₃₋₆cycloalkyl, phenyl, and 5- or 6-membered heteroaryl, any of which isoptionally substituted with one or more R₁₇ groups.
 15. The compound asrecited in claim 1, wherein R₆ is aminomethyl; and R₇ is selected fromhydroxy, C₁₋₄alkyl, C₁₋₄hydroxyalkyl, C₃₋₆cycloalkyl, phenyl, and 5- or6-membered heteroaryl.
 16. The compound as recited in claim 1, whereinR₆ is amino; and R₇ is selected from amido, C₁₋₄alkyl, C₁₋₄hydroxyalkyl,C₃₋₆cycloalkyl, phenyl, and 5- or 6-membered heteroaryl, any of which isoptionally substituted with one or more R₁₇ groups.
 17. The compound asrecited in claim 1, wherein R₆ is amino; and R₇ is C₁₋₄hydroxyalkyl. 18.The compound as recited in claim 1, wherein R₁ is selected fromC₆₋₁₀aryl and a 5-9 membered heteroaryl group containing 1 to 4heteroatoms or groups independently selected from N, C(O), O, and S;said aryl or heteroaryl of R₁ is optionally substituted with 1 to 5 R₁₂groups independently selected from halo, hydroxy, alkoxy, amino,C₁₋₄alkylamino, C₁₋₄dialkylamino, cyano, C₁₋₄alkyl.
 19. The compound asrecited in claim 1, wherein R₁ is selected from:

and each R₁₂ is independently selected from halo, hydroxy, amino,methylamino, dimethylamino, cyano, C₁₋₄alkyl, and C₁₋₄alkoxy.
 20. Thecompound as recited in claim 19, wherein R₁ is selected from:


21. The compound as recited in claim 20, wherein each R₁₂ isindependently selected from halo, hydroxy, C₁₋₄alkyl, and C₁₋₄alkoxy.22. The compound as recited in claim 1, wherein R₁ is selected frompyridyl, piperazinyl, pyrimidinyl, pyrazolyl, and pyridazinyl.
 23. Thecompound as recited in claim 1, wherein R₁ is phenyl.
 24. The compoundas recited in claim 1, wherein the structure is selected from:


25. The compound as recited in claim 24, wherein R₆ is selected fromamino, C₁₋₄aminoalkyl, and C₁₋₄alkylamino; R₇ is selected from hydrogen,cyano, amido, halo, and hydroxy, or is selected from C₁₋₄alkyl, andC₁₋₄hydroxyalkyl, any of which is optionally substituted with one ormore R₁₇ groups; and each R₁₇ is independently selected from amino,halo, and hydroxy.
 26. The compound as recited in claim 1 wherein thestructure is selected from:

or a salt or tautomer thereof.
 27. The compound as recited in claim 1,wherein the structure is selected from:

or the enantiomer of any one of the above structures, or a salt ortautomer of any of the above structures, or a salt or tautomer of theenantiomer of any one of the above structures.
 28. The compound asrecited in claim 1, wherein the structure is selected from:

or a salt or tautomer of any of the above structures.
 29. The compoundas recited in claim 1, wherein the structure is


30. The compound as recited in claim 1, wherein the structure is


31. The compound as recited in claim 1, wherein the structure is


32. The compound as recited in claim 1, wherein the structure is


33. The compound as recited in claim 1 wherein the structure is selectedfrom:

or a salt or tautomer thereof.
 34. The compound as recited in claim 1wherein the structure is selected from:

or a salt or tautomer thereof.
 35. A compound as recited in claim 1 foruse as a medicament.
 36. A compound as recited in claim 1 for use in thetreatment of a disease driven by one or more PTPN11 mutations.
 37. Thecompound as recited in claim 36, wherein the disease is selected fromNoonan Syndrome or LEOPARD Syndrome.
 38. A compound as recited in claim1 for use in the treatment of cancer.
 39. The compound as recited inclaim 38, wherein the cancer is selected from leukemia, melanoma, breastcancer, and colon cancer.
 40. A compound as recited in claim 1 for usein the manufacture of a medicament for the prevention or treatment of adisease or condition ameliorated by the inhibition of PTPN11.
 41. Apharmaceutical composition comprising a compound as recited in claim 1together with a pharmaceutically acceptable carrier.
 42. A method ofinhibition of PTPN11 comprising contacting PTPN11 with a compound asrecited in claim
 1. 43. A method of treatment of a PTPN11-mediateddisease comprising the administration of a therapeutically effectiveamount of a compound as recited in claim 1 to a patient in need thereof.44. The method as recited in claim 43 wherein the disease is cancer. 45.The method as recited in claim 44 wherein the cancer is selected frombreast cancer, colon cancer, leukemia, and melanoma.
 46. The method asrecited in claim 43 wherein the disease is selected from Noonan Syndromeor LEOPARD Syndrome.
 47. A method of treatment of a PTPN11-mediateddisease comprising the administration of: a. a therapeutically effectiveamount of a compound as recited in claim 1; and b. another therapeuticagent.
 48. The method as recited in claim 47 wherein the disease iscancer.
 49. The method as recited in claim 48 wherein the cancer isselected from breast cancer, colon cancer, leukemia, and melanoma. 50.The method as recited in claim 47 wherein the disease is selected fromNoonan Syndrome or LEOPARD Syndrome.